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Functional Foods in Cancer Prevention and Therapy
 0128161515, 9780128161517

Table of contents :
Cover
Functional Foods in Cancer
Prevention and Therapy
Copyright
Contributors
Author biographies
1
Natural remedies and functional foods as angiogenesis modulators
Angiogenesis definition and background
Molecular mechanism of angiogenesis
Screening methods of angiogenesis modulators
Natural angiogenesis modulators
Concluding remarks and future perspective
References
2
Targeted cancer therapy with bioactive foods and their products
Introduction
Pathophysiology of cancer
Classification of anticancer bioactive foods
Classification of anticancer bioactive foods based on origin
Anticancer bioactive foods of plant origin
Anticancer bioactive foods of animal origin
Anticancer bioactive foods of microbial origin
Classification of anticancer bioactive foods based on the mechanism of action
Antimetastatic bioactive foods
Antiproliferative bioactive foods
Bioactive foods inducing apoptosis
Antiangiogenic bioactive foods
Anticancer bioactive foods scavenging free radicals
Anticancer bioactive foods inhibiting matrix metalloproteinases
Anticancer bioactive foods inducing DNA methylation
Classification based on the chemical nature of anticancer bioactive food components
Anticancer bioactive foods with phenolic components
Anticancer bioactive foods with flavonoid components
Anticancer bioactive foods with carotenoid components
Anticancer bioactive foods with saponin components
Anticancer bioactive foods with fatty acid components
Anticancer bioactive foods with sulforaphane components
Anticancer bioactive foods with dietary fiber components
Conclusion
References
3
Natural compounds and anticancer effects: The whole is greater than the sum of its parts
Cancer research
Anticancer products from nature
Main natural cancer therapeutics
Tubulin-binding agents
Topoisomerase inhibitors
Other drugs from natural sources
Cancer prevention or natural chemopreventive agents
An example of synergistic interaction
Conclusion
References
4
Relationship between functional food and tumor metabolism
Introduction: Functional foods
Functional foods exert their beneficial effects mostly through cellular metabolism
Metabolic dysregulation in tumor cells
Tumor metabolism: Glycolysis and acidosis
Tumor metabolism: Mitochondria and altered TCA cycle fate
Functional foods: Metabolic reprogramming in tumor cells and emerging concepts in therapeutic strategies
Conclusion
References
5
Adiponectin-enhancing dietary constituents in cancer prevention
Introduction
Inflammation in carcinogenesis
Antiinflammatory adiponectin and allied compounds
Omega-3 PUFAs and adiponectin
Conclusion
References
6
Lentils (Lens culinaris L.): A candidate chemopreventive and antitumor functional food
Introduction
Anticancer chemical constituents of lentils
High polar phytochemicals
Polyphenols
Proteins and bioactive peptides
Lectins
Defensin
Protease inhibitors
Phytosterols
Saponins
Medium polar phytochemicals
Flavonoids
Less polar phytochemicals
Squalene
Insoluble lentils products
Fibers
Phytic acid (hexaphosphorylated inositol, IP6)
Epidemiological evidence on the chemopreventive potential of lentils
Experimental evidence
In vivo studies
In vitro studies
Remarks and conclusions
References
7
Evidence for anticancer properties of honey with emphasis on mechanistic overview
Introduction
Chemistry of honey
Pharmacological uses of honey
Honey stimulates the immune system
Honey as antioxidants
Honey as antiinflammatory agents
Antimutagenic effects of honey
Antiapoptotic effects of honey
Antiproliferative effects of honey
Conclusion
References
8
Curcumin in cancer prevention and therapy
Introduction
Carcinogenesis, chemoprevention, and plant-derived products
Curcumin: A super magical chemopreventive and therapeutic agent
Hallmarks of cancer and molecular targets for chemoprevention and treatment
Cell cycle and curcumin
Cell death (apoptosis) and curcumin
Molecular mechanisms of curcumin action
Mitochondrial activation
Caspase activation
Oxidative stress
Direct DNA damage
P53/p21 pathway
NF-κB and AP-1 signaling pathways
Akt (protein kinase B) pathway
STAT signaling
Nrf2 signaling
β-Catenin
Growth factors
Enzymes
Ornithine decarboxylase
Thioredoxin reductase
COX and LOX
Protein kinase
Proteasome
Effect of curcumin on normal cells
Resistance to conventional chemotherapy
Conclusion
References
9
Usefulness of grape seed polyphenols in the prevention of skin cancer: A mini review
Introduction
Grape seed and their polyphenols
Grape seed polyphenols are effective in prevention of cancer
Grape seed polyphenols are effective in preventing UV-induced skin carcinogenesis
Conclusion
References
10
Indian herbal medicine and their functional components in cancer therapy and prevention
Introduction
Turmeric (Curcuma longa)
Bioactive compounds in turmeric
Curcumin in cancer prevention
Ginger (Zingiber officnale Roscoe)
Anticancer properties
Tamarind (Tamarindus indica L.)
Onion (Allium cepa L.) and garlic (Allium sativum L.)
Moringa (Moringa oleifera Lam)
Neem (Azadirachta indica)
Pomegranate (Punica granatum)
Amla (Phyllanthus emblica L.)
Sugar beet (Beta vulgaris)
Bitter gourd (Momordica charantia)
Future research needed
References
Further reading
11
Antioxidant phytochemicals in cancer prevention and therapy-An update
Introduction
Cancer: Public health burden and ACM
Cancer and oxidative stress
Antioxidant phytochemicals (APH)
APH in cancer prevention
APH in cancer therapy
Metabolic fate of APH
APHs as prooxidants
Conclusion
Acknowledgments
References
Further reading
12
Prooxidant anticancer activity of plant-derived polyphenolic compounds: An underappreciated phenomenon
Introduction
Cancer chemoprevention and polyphenols
A copper-mediated prooxidant anticancer mechanism of polyphenols
Oxidative DNA breakage induced by polyphenols in the presence of copper ions in vitro
Polyphenols mobilize nuclear copper to mediate prooxidant DNA damage
Inducing high copper levels in lymphocytes leads to increase in polyphenol-induced DNA breakage
Polyphenol induced cell death in cancer cells occur through mobilization of intracellular copper and generation of ROS
Copper-mediated prooxidant anticancer action of polyphenols is augmented at acidic pH microenvironment associated with tumors
Making sense of the prooxidant action of polyphenols
Conclusion
References
13
Plant-based products in cancer prevention and treatment
Introduction
Cancer and oxidative stress
Antioxidant therapeutics in cancer
Phytochemicals as anticancer therapeutics
Cellular mechanism of actions of phytochemicals
Nutraceuticals as anticancer therapy
Therapeutic efficacy and purification of anticancer phytochemicals
Development and use of synthetic analogs to plant-derived substances
Conclusion
References
Further reading
14
Overview of probiotics in cancer prevention and therapy
Introduction
General health benefits of probiotics
Probiotics in immune modulation
Probiotics, Helicobacter pylori, and stomach cancer
General influence of gut microbiome on cancer
Probiotics in colorectal cancer
Probiotics and upper body cancers
Delivery systems for probiotics
Dairy-based probiotic foods
Meat-based probiotic foods
Plant-based probiotic yogurt
Encapsulation of probiotics for better delivery
Plant-based, nondairy probiotic foods
Conclusion
References
Further reading
15
Plant-derived functional foods with chemopreventive and therapeutic potential against breast cancer: A review of the precl ...
Introduction
Antioxidant and genoprotective effects of phytochemicals
Possible targets of phytochemicals in breast cancer cell signaling
Cell cycle
Apoptosis
Angiogenesis
Cancer stem cells
Epigenome
Anticancer properties of plant-derived functional foods in preclinical breast cancer research
In vitro studies
In vivo studies
Epidemiological and clinical breast cancer studies
Discussion and future directions
Conclusion
Acknowledgment
References
16
Complementary and alternative medicine (CAM) in head and neck malignancy and its impact on treatment
Introduction
Reasons for use of CAM
Types of CAM-Natural products
Mind body practices
Acupuncture
CAM and pain
Selected randomized control trials for CAM in head and neck
Application of CAM in head and neck malignancy
Effects of CAM on head and neck malignancy treatment
Integration of CAM in tertiary hospital
Conclusion
References
Further reading
17
Targeting cancer stem cells with phytoceuticals for cancer therapy
Introduction
CSC generation
Targeting signaling pathways of CSCs
Wnt/β-catenin signaling
Sonic hedgehog signaling
Notch signaling
KRAS signaling
Targeting the CSC niche
CSCs in hypoxia
CSCs in perivascular niche
CSCs in inflammatory niche
CSCs in tumor stromal tissue niche
CSCs and therapy resistance
Phytoceuticals and their analogues with the potential to target CSCs
Curcumin
Resveratrol
Epigallocatechin gallate (EGCG)
Isoflavones
Sulforaphane
Conclusion and future perspectives
References
18
Nutrigenomics and functional food: Implications for cancer prevention and treatment
Nutrigenomics and functional food
Nutrigenomic and functional foods: Cancer prevention
Nutrigenomic and functional foods: Cancer treatment
Final considerations
References
Further reading
19
Harnessing personalized nutrigenomics for cancer prevention and treatment through diet-gene interaction
Introduction
The emerging field of nutrigenomics
Nutrient-gene interactions
Interaction of diets and genes in cancers
Impact of dietary modification in cancer
Glycemic index and cancer risk
Nutritional epigenomics
Dietary factors, cancer prevention, and treatment: Preclinical and clinical studies
Conclusion
References
20
Functional foods in cancer prevention and therapy: Recent epidemiological findings
Introduction
Foods and dietary components for possible associations with increasing cancer risk
Functional foods and their role in cancer
Polyphenols and carotenoids
Curcumin
Lycopene
Isoflavone
Green tea
Mushrooms
Fiber
Dietary fat
High protein diet
Vitamin and minerals
Multivitamins
Vitamin D and calcium
B Vitamins
Future perspective of functional foods in cancer management, especially in children and aged people
Conclusion
References
21
Food and nutrition in cancer survivors: LONGLIVE® lifestyle-Current guidelines and mechanisms
Introduction
Why are safe foods needed in cancer survival?
What is the LONGLIVE lifestyle for survivors?
Cancer-causing food additives
Carcinogenic chemicals
Food exposure to ionized radiation causes cancer
Contaminated foods with bacteria and viruses
Cancers of genetic origin
Physiological factors cause cancer
Endocrine and hormonal changes
Immune deficiency and immunity dysfunction
Obesity and foods
Discipline, positive thoughts, healthy rules, diet control, and good behavior
Cancer causing contaminants in foods: FDA and ACI guidelines
Regulatory guidelines by federal, governmental, or international agencies for cancer survivors
WHO guidelines on foods
USDA Food Safety and Inspection Service
ACS guidelines for cancer survivors
ACI guidelines for cancer prevention
ADA guidelines to cancer survivors and eating plan
NCI guidelines on the role of phytochemicals and nutraceuticals: Diet and nutrition in the development of cancer
American Institute of Cancer Research Guidelines on cancer
AICR guidelines on clean foods to cancer survivors
AICR guidelines: Cancer prevention and cancer risk reduction
National Institute of Nutrition Guidelines on cancer prevention
Emerging role of healthy diet and LONGLIVE lifestyle for cancer survivors
Diet and nutrition's impact on carcinogenesis at the molecular level
Scientific basis
Mechanisms
Free radicals in foods: Oxidative stress
Chromatin modification
DNA methylation
Epigenetic alterations in tumor progression
DNA methylation in histone
2-Cyclooxygenase (COX)-2 and LPS selective inhibitors in bioactive foods
Wnt gene signaling pathways and ubiquitin genes
Laminin receptor downregulation
Role of nitrates, nitrites, and heme iron regulation
Immune response loss
Oxidant action
Nutraceutical anticancer mechanism
Probiotic and prebiotic action
Vitamin D, multivitamins, and antioxidants as anticancer in cancer survivors
Cancer survivors can follow opulent LONGLIVE lifestyle
Guideline to physicians and nurses on longevity among cancer survivors
New protocol
Conclusion
Acknowledgments
References
Further reading
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Z
Back Cover

Citation preview

Functional Foods in Cancer Prevention and Therapy

Functional Foods in Cancer Prevention and Therapy Edited by

Yearul Kabir

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-816151-7 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Charlotte Cockle Acquisitions Editor: Megan Ball Editorial Project Manager: Susan Ikeda Production Project Manager: Poulouse Joseph Cover Designer: Harris Greg Typeset by SPi Global, India

Contributors Debopam Acharya Department of Zoology, Jogamaya Devi College, Kolkata, India Mohammed Adnan Father Muller Medical College, Mangalore, India Dina Alkandari Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait Asfar S. Azmi Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States Nandakishore Bala Father Muller Medical College, Mangalore, India Manjeshwar Shrinath Baliga Mangalore Institute of Oncology, Mangalore, India Md. Rakibul Hassan Bulbul Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong; Institute for Developing Science and Health Initiatives (ideSHi), Centre for Medical Biotechnology (CMBT), Institute of Public Health Building, Dhaka, Bangladesh Sajib Chakraborty Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh Jae Hyun Cho Cancer Research Institute; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea Vera Elizabeth Closs Institute of Geriatrics and Gerontology, Cardiometabolic Risk, Aging, and Nutrition Study Group (GERICEN), Pontifı´cia Universidade Cato´lica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil Jan Danko Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic Mo’ez Al-Islam E. Faris Department of Clinical Nutrition and Dietetics, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates Maria Gabriela Valle Gottlieb Biomedical Gerontology Graduate Program, School of Medicine, Institute of Geriatrics and Gerontology, Pontifical Catholic University of Rio Grande do Sul (IGG-PUCRS), Porto Alegre, Brazil Pankaj Gupta School of Medical and Allied Sciences, K. R. Mangalam University, Gurgaon, India xv

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Contributors

Sheikh Mumtaz Hadi Department of Biochemistry, Aligarh Muslim University, Aligarh, India Youngjin Han Department of Agricultural Biotechnology, Seoul National University; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Fazlul Huq Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia S.M. Rafiqul Islam National Cancer Institute (NCI), National Institute of Health, Bethesda, MD, United States Arunporn Itharat Center of Excellence in Applied Thai Traditional Medicine Research (CEATMR), Thammasat University, Bangkok, Thailand Vilma Maria Junges Integrated Center for Obesity Treatment (CINTRO), Porto Alegre, Brazil Yearul Kabir Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh Faizan Kalekhan Mangalore Institute of Oncology, Mangalore, India Martin Kello Department of Pharmacology, Faculty of Medicine, University of Pavol Jozef Sˇafa´rik, Kosˇice, Slovak Republic Md. Abdul Khaleque Department of Biochemistry and Microbiology, North South University, Dhaka, Bangladesh Husain Y. Khan Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States Peter Kubatka Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic Avinash Kundadka Kudva Department of Biochemistry, Mangalore University, Mangalore, India Norhafiza Mat Lazim School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Malaysia Ki Won Lee Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea Alena Liskova Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic Simona Martinotti DiSIT-Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale, Alessandria, Italy

Contributors

xvii

Robert Moffatt Department of Human Nutrition, Food and Exercise Science, Florida State University, Tallahassee, FL, United States Mohammad G. Mohammad Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates Ramzi M. Mohammad Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States Jan Mojzis Department of Pharmacology, Faculty of Medicine, University of Pavol Jozef Sˇafa´rik, Kosˇice, Slovak Republic Meher Un Nessa Environmental Science Discipline, Life Science School, Khulna University, Khulna, Bangladesh; Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia Francisco J. Olivas-Aguirre Departamento de Ciencias de la Salud, Universidad de xico Sonora (Campus Cajeme), Ciudad Obrego´n, Me Karkala Sreedhara Ranganath Pai Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India Michael L.J. Pais Father Muller Medical College, Mangalore, India In Sil Park Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea Mohammad Mostafizur Rahman Laboratories of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States Md. Atiar Rahman Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh Atiqur Rahman Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh Elia Ranzato DiSIT-Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale, Vercelli, Italy Suresh Rao Mangalore Institute of Oncology, Mangalore, India Pratima Rao Mangalore Institute of Oncology, Mangalore, India Amitabha Ray Lake Erie College of Osteopathic Medicine, Seton Hill University, Greensburg, PA, United States Simon Sajan Mangalore Institute of Oncology, Mangalore, India

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Contributors

Raquel Seibel Biomedical Gerontology Graduate Program of the School of Medicine, Pontifical Catholic University of Rio Grande do Sul (IGG-PUCRS), Porto Alegre, Brazil Rakesh Sharma Innovations and Solutions Institute, AMET University, Chennai; SMMH Government Medical College, Saharanpur, Uttar Pradesh, India Towfida Jahan Siddiqua International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh Jiwan S. Sidhu Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait Peter Solar Department of Medical Biology, Faculty of Medicine, University of Pavol Jozef Sˇafa´rik, Kosˇice, Slovak Republic Zuzana Solarova Department of Pharmacology, Faculty of Medicine, University of Pavol Jozef Sˇafa´rik, Kosˇice, Slovak Republic Sameh Soliman Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates Yong Sang Song Department of Agricultural Biotechnology, Seoul National University; Cancer Research Institute, Seoul National University College of Medicine; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea Arvind Trivedi SMMH Government Medical College, Saharanpur, Uttar Pradesh, India Mehmet Varol Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey dicas, Universidad Auto´noma de Abraham Wall-Medrano Instituto de Ciencias Biome ´ ´ Ciudad Juarez, Ciudad Juarez, Mexico Tasleem A. Zafar Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait Pavol Zubor Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic Anthony Zulli Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia

Author biographies Mehmet Varol received his first bachelor’s degree in Biology in 2010 and the second in Business Administration in 2015 at Anadolu University, Turkey. He received his master’s degree in 2013 by completing his thesis, “Investigation of protective effect of lichen acids against ultraviolet rays,” and received his Ph.D. in 2017 with his dissertation on “Investigation of the angiogenesis-targeted treatment potentials of the small molecule structured natural compounds by epigenetic approach and molecular mechanisms on tumor development and invasion.” He currently continues his academic career as a research associate at the Mugla Sitki Kocman University, Turkey. His research interests include but are not limited to natural drug sources, drug design and discovery, controlled drug delivery systems, photodynamic cancer therapy, angiogenesis and related therapies, photo-biological experiments, reactive oxygen species, and intracellular molecular dynamics. Pankaj Gupta earned his Ph.D. in the area of Marine Pharmacology from All India Institute of Medical Sciences, New Delhi. He is presently working as an assistant professor at K.R. Mangalam University, Gurgaon, Haryana. He has published more than 30 papers in reputed national/international journals as well as 2 chapters in international books; he has also received two patents. He was the former vice chairman of the Society of Young Scientists at AIIMS. He is presently serving as the editor for two international scientific journals: the Journal of Traditional Medicine and Clinical Naturopathy and Natural Product Chemistry and Research, published by Omics group, United States. He is also the reviewer for various national/international scientific journals such as Pharmaceutical Biology, Phytomedicine, Indian Journal of Physiology and Pharmacology, Natural Product Research, etc. He served as a resource person in several national/international conferences such as the Indian Pharmaceutical Congress-2018, PHYTOCON-2018, SYSCON-2018, etc., and has cocoordinated several symposia, conferences, bioanalytical hands-on workshops, and QIP, and is the recipient of several national/international travel fellowships. Elia Ranzato has a degree in Biological Sciences from the University of Piemonte Orientale, summa cum laude, and a Ph.D. from the University of Piemonte Orientale. His research activity aims at the characterization of cellular and molecular levels of natural compounds. Simona Martinotti has a degree in Biology from the University of Piemonte Orientale, summa cum laude, and a Ph.D. from the University of Piemonte Orientale. Her research activity is devoted to characterizing at the physiological level the action of natural compounds. xix

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Author biographies

Md. Abdul Khaleque is a prominent molecular biologist and biotechnologist with over a decade of experience in basic research, teaching, and industrial settings. He earned his Ph. D. in Molecular Genetics from Kumamoto University, Japan, in 2002, and his master’s in Biochemistry and Molecular Biology from Dhaka University, Bangladesh, in 1991. He is currently working at North South University (NSU), Dhaka, Bangladesh, as a professor of Biochemistry in the Department of Biochemistry and Microbiology. Prior to his current position, he served as the chair of the same department for more than 5 years. Before joining NSU, Khaleque worked with Invitrogen Corporation in California, United States, where he worked closely with quality assurance and quality control to identify potential areas of improvement as they pertain to regulatory or scientific issues. Prior to Invitrogen, he worked at Boston University and Harvard Medical School, Massachusetts, United States. In both institutes, he was actively involved in cancer research directed at understanding the role of heat shock proteins in cancer metastasis. He was also involved with various research projects at national and internationally recognized research organizations such as ICDDRB and BIRDEM. Over the past 20 years, his research has focused on many contemporary issues related to cancer biology, mitochondrial protein transport, the regulation of protein phosphorylation in signal transduction pathways, and the antioxidant contents of Bangladeshi fruits and vegetables. Mohammad Mostafizur Rahman is a biochemist and molecular biologist with extensive experiences in basic research and teaching. He graduated from the Biochemistry Department of Dhaka University, Dhaka, Bangladesh, in 1992. He worked as a research scientist at the International Center of Diarrheal Disease Research, Bangladesh (ICDDRB) until 1999 before moving to the United States. He completed his Ph.D. in 2010 from the Department of Genetics and Cellular Biology, University of Georgia, United States. Currently he is working as a scientist at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Laboratory of Cell and Molecular Biology, the National Institutes of Health, Maryland, United States. Amitabha Ray completed his graduation in Medicine (MBBS) from the University of Calcutta, his postgraduate work (M.D.) from B.H.U., Varanasi, and his Ph.D. from J.M.I., New Delhi, India. He pursued his postdoctoral research in Dr. Margot P. Cleary’s laboratory at the Hormel Institute, the University of Minnesota, United States. In Cleary’s lab, he worked primarily on the role of obesity and the interactions between leptin and adiponectin in breast cancer pathology. Currently, he is working with LECOM at Seton Hill University, Greensburg, Pennsylvania, as an associate professor. Debopam Acharya received his Ph.D. from Jadavpur University, Kolkata, India, in 2009. He worked under the mentorship of Dr. Tarun K. Dhar at the Indian Institute of Chemical Biology (CSIR), Kolkata, on “Improved immunoassay strategies for the determination of mycotoxins and steroid hormones.” His research interests includes immunochemistry, high throughput analytical device development, and invertebrate immunology. He has been teaching zoology to undergraduate students since 2010 and currently holds the position of assistant professor and head of the Zoology Department at Jogamaya Devi College, Kolkata.

Author biographies

xxi

Mo’ez Al-Islam E. Faris has completed his bachelors and masters degrees in Nutritional and Food Sciences from the University of Jordan. He pursued his Ph.D. from the same university in dietary chemoprevention against chemically induced colon cancer using lentils as a traditional plant food, and thereafter worked on camel milk as a traditional food in the Arabian area. Then he expanded his work to include the chemopreventive effect of lentils against human breast and colon cancer cell lines. Recently, Faris extended his work to include intermittent fasting as a putative dietary modification applied in modulating proinflammatory and antiinflammatory cytokines. Now, he is expanding his research to include metabolic, metabolomics, lipidomics, genetic, and epigenetic mechanisms involved in intermittent fasting. Sameh Soliman received his bachelors and masters degrees in Pharmaceutical Sciences. He received his Ph.D. from the University of Guelph, Canada, in the chemical ecology of natural products and its role in host-microbe interactions. Then he did a postdoctoral fellowship in mycotoxin manipulation and detoxification at Canadian Federal Labs, followed by another postdoctoral fellowship at UCLA in chemical and biomolecular engineering of natural products. At UCLA Medical School, he was trained in infectious diseases, pathogenesis mechanisms, and possible ways in diagnosis and treatment. His research interests can be categorized in two major subjects: natural products as potential medicines and microbial products, either as toxins or medicines. For more than 18 years, he received extensive training experience in natural products either from plants or microbes, including their chemical ecology and role in nature. Now he is developing a line of research to discover effective antimicrobials from UAE natural resources and to optimize their structures and activities. Mohammad G. Mohammad received his B.Sc. in medical laboratory technology and his M.Sc. degree in Biological Sciences, with his research focusing on cellular immune responses against mucosal fungal infections. Then, during his Ph.D. at Macquarie University, Sydney, Australia, Mohammad extended his interest into developmental and comparative cellular immunology. Since commencing his postdoctoral fellowship at St. Vincent’s Hospital Venter of Applied Medical Research in 2010, he contributed to uncovering novel mechanisms of disease progression and cellular central nervous system immunoregulation that are amenable to therapeutic targeting. Also, Mohammad has contributed to the identification of a forebrain migration pathway of dendritic cells capable of regulating anti-CNS immunity. The major thrust of his research is in vitro and animal models of disease. Mohammad is currently pursuing his long-term interest in developmental cellular immunity and its roles in neuroinflammation at the Sharjah Institute of Medical Research. Avinash Kundadka Kudva earned his Ph.D. in Biochemistry from Karnatak University, Dharwad, India, in 2012. Later, during his postdoctoral fellowship at Pennsylvania State University, United States, he investigated the importance of lipid mediators, especially omega-3 derived eicosanoids, in regulating the cellular metabolism. In 2015, he moved to his current position at Mangalore University, where he continues to study the role of micronutrients in relation to redox-regulated processes in inflammation and cancer development. His research interests include oxidative stress, redox signaling, and micronutrients, notably selenium and flavonoids.

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Author biographies

Suresh Rao is a senior radiation oncologist and the director of Clinical and Administration at the Mangalore Institute of Oncology. Rao completed his undergraduate degree (Medicinae Baccalaureus Baccalaureus Chirurgiae, MBBS) and master’s in radiotherapy (MD radiotherapy) from the prestigious Kasturba Medical College Manipal. Rao has the unique distinction of starting two radiation oncology centers in the world: Father Muller’s Medical College Mangalore and at the Mangalore Institute of Oncology. He has treated more than 25,000 patients. His research interests are in the areas of novel treatment and the integration of alternative systems of medicine for better recovery posttreatment. He has published around 50 scientific articles, journals, and textbooks. Pratima Rao is a senior dental professional and oral pathologist at the Mangalore Institute of Oncology. She graduated from Nair Hospital Dental College, Mumbai, and got her master’s from MAHE Manipal. She is vastly experienced in treating the unique dental and oral health care needs of patients with various forms of cancer. Her research interests are in the prevention of oral cancer and the mitigation of treatment-induced ill effects. She has published more than 25 articles in journals of repute. In addition to this, she also heads the cancer education and awareness cell of the Mangalore Institute of Oncology and is active in community education and cancer screening programs. Michael L.J. Pai is currently pursuing his final year of his undergraduate degree in Medicinae Baccalaureus Baccalaureus Chirurgiae, (MBBS), at Father Muller Medical College and Hospital. He has been interested in the field of medical science and research and has coauthored three textbook chapters, three research papers, and one review article. He was also an active member in the Student Wing of South India Unit of UNESCO Chair in Bioethics (Haifa). Mr. Pais has presented a paper at an international conference and aspires to specialize in cardiooncology. Mohammed Adnan is pursuing his undergraduate degree in Medicinae Baccalaureus Baccalaureus Chirurgiae, (MBBS) at Father Muller Medical College and Hospital. He is a recipient of the prestigious Short Term Studentship Program from the Indian Council of Medical Research for 2016. He is also an active member of the Student Wing of South India Unit of UNESCO Chair in Bioethics (Haifa). Mr. Adnan has presented a paper at an international conference and aspires to specialize in oncology. Karkala Sreedhara Ranganath Pai completed his B.Pharm. in 1994 from the National College of Pharmacy, Shimoga (Kuvempu University), his M.Pharm. in 1997 from Manipal College of Pharmaceutical Sciences, Mangalore University, and his Ph.D. from Kuvempu University in 2002. He has been working in academics for the last 22 years and is currently the head and professor of Pharmacology at Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal. His areas of research are cancer and metabolic disorders and he has guided 38 M.Pharm. and 8 Ph.D. candidates. He has published more than 75 articles in national and international journals and chapters in books. Manjeshwar Shrinath Baliga is in charge of research at the Mangalore Institute of Oncology. He received his Ph.D. in radiation biology from Kasturba Medical College, Manipal,

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India, with research on the anticancer and radiomodulatory properties of novel agents. He received advanced training at Tata Memorial Centre, Mumbai, and a postdoctoral fellowship at the University of Alabama, Birmingham, United States, as well as a second postdoctorate from the University of Illinois, Chicago, in areas of cancer prevention and metastasis. His research interests are in the areas of cancer chemoprevention, radio modulation, cancer ethics, and health economics. He has published around 225 scientific articles, journals, and textbooks. Meher Un Nessa completed her B.Sc. (Honors) and M.Sc. in Biochemistry from the University of Dhaka, Bangladesh, and a second M.Sc. in Applied Biomolecular Technology from the University of Nottingham, the United Kingdom. Her Ph.D. in Medicine is from the University of Sydney, Australia. Her current research is focused on drug metabolism with special reference to anticancer drugs and tumor active natural products. She has presented her research at major international conferences and has a good number of research papers and review articles in peer-reviewed journals. Fazlul Huq holds B.Sc. (Honors) and M.Sc. degrees in Chemistry from the University of Dhaka and a Ph.D. in Chemical Crystallography from Imperial College London. His current research is focused on drug discovery and combination therapy as applied to ovarian and colorectal tumor models with special emphasis on tumor active phytochemicals and other compounds from natural sources. He has presented research at major international conferences. He has more than 250 original research papers and review articles in peer-reviewed journals. He has supervised 26 Ph.D. and 5 masters candidates by research to successful completion. He is an internationally acclaimed poet with more than 25,000 compositions. His poetry can be accessed at Allpoetry.com where he writes with the name Jujube. Faizan Kalekhan completed his Medicinae Baccalaureus Baccalaureus Chirurgiae (MBBS) at Father Muller Medical College and Hospital in 2015. Later, he worked as a duty doctor and research assistant at the Mangalore Institute of Oncology under Dr. Suresh Rao and Dr. M.S. Baliga. Currently, he is pursuing his postgraduation work in the Department of Dermatology, Venereology, and Leprosy at Yenepoya Medical College Hospital, Mangalore. He is a recipient of the prestigious short-term studentship program from the Indian Council of Medical Research for three consecutive years from 2012 to 2014, and has presented papers in international conferences. Nandakishore Bala is a senior dermatologist of professor grade at Father Muller Medical College and Hospital. He completed his Medicinae Baccalaureus Baccalaureus Chirurgiae (MBBS) from the prestigious Mysore Medical College and did postgraduation work in Dermatology, Venereology, and Leprosy at Father Muller Medical College and Hospital in 1978 and 1993, respectively. Bala is a well-known dermatologist for his contribution to Hansen’s disease. He has been a mentor for more than 250 students and a postgraduate guide for 20 dermatology fellows. He has published more than 50 scientific articles in international journals of repute and is on the editorial and review boards of various journals.

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Author biographies

Simon Sajan completeted his Medicinae Baccalaureus Baccalaureus Chirurgiae (MBBS) at Father Muller Medical College and Hospital in 2018. Currently, he is working as a duty doctor and research assistant at the Mangalore Institute of Oncology under Dr. Suresh Rao and Dr. M.S. Baliga. Sajan has four research papers and has presented papers in national conferences. He aspires to specialize in oncology. Jiwan S. Sidhu, Alexander von Humboldt Foundation Fellow, Germany, obtained his B.Sc. Agri and A.H. from Punjab Agril University, Ludhiana, India; M.Sc. in Food Technology from IFTTC, CFTRI, Mysore, India; Ph.D. in grain science from Kansas State University, Manhattan, Kansas, United States, and postgraduate diploma in business management from PAU, Ludhiana. Served as Scientist-E (professor level position), CFTRI, Mysore, India, from May 2, 1984, to September 5, 1986; Visiting Prof. Department of Grain Science and Industry, Kansas State University, September 1992-March 1993; served PAU, Ludhiana for about 21 years, also as Professor and Head, Department of Food Science and Technology, from Aug. 22, 1988, to Aug. 21, 1992; Research Scientist, Biotechnology Department, KISR, Kuwait, from May 9, 1993, to July 31, 2004; Professor of Food Science, College of Life Sciences, Kuwait University, since September 19, 2004, Director Masters’ Programs since September 2012. Fellow, Association of Food Scientists and Technologists (I), Mysore, India, since 1995 and Humboldt Fellow (Germany). Has guided 14 M.Sc. and 2 Ph.D. students, and currently guiding 5 M.Sc. students. Has published 95 research papers in peerreviewed journals, 30 book chapters in United States books, and 69 general papers in various areas of food science and technology. Tasleem A. Zafar, working as Associate Professor and Director of the Masters’ Program at Kuwait University, earned her Ph.D. in Foods and Nutrition at Purdue University, West Lafayette, Indiana, United States. She has also worked as a postdoctoral fellow and research associate at Purdue University and the University of Toronto. Her primary research interest focuses on achieving breakthroughs for the epidemic ailments of obesity and diabetes through food formulations and individual micronutrient deficiencies through manipulation of energy components to enhance insulin-sensitizing effects and the satiety power of meals. She also works on mineral metabolism and bone health status. Dr. Zafar has published more than 20 original research articles in peer-reviewed journals and contributed chapters to four scholarly books on Fruits, Vegetables, and Functional Foods, published by Wiley-Blackwell Publishing, New York, United States, and by IGI Global (formerly Idea Group Inc.), United States. She is an honorary editor of the Pakistan Journal of HomeEconomics (PJHE) and has served as an honorary reviewer for the Journal of Medicinal Foods, the Journal of Food Science and Technology, and the British Journal of Nutrition. Dina Alkandari, currently working as Assistant Professor in the Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, since January 2012, has obtained her B.Sc. and M.Sc. degrees in Microbiology from Kuwait University, and her M.Sc. and Ph.D. degrees in Food Science from the University of Reading, Reading, Berkshire, United Kingdom. At Kuwait University, she teaches food microbiology, food safety, food regulations, food quality assurance, and quality control in the food industry. She has

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published seven research papers in international journals of repute and presented three papers in international conferences. As a resource person in food control, she has participated in more than a dozen international conferences. She has guided two M.Sc. students and is also guiding two more students. She has actively participated and has made outstanding contributions in the development of graduate programs in Food Science and Nutrition in the Department at this University. Abraham Wall-Medrano, chemist-pharmaceutical biologist from the Autonomous University of Guadalajara (Mexico), doctor in Nutritional Sciences from the Center for Research in Food and Development, A.C. (Mexico). Research-professor at the Autonomous University of Ciudad Juarez (Biomedical Sciences Institute). His research interests are community health/physical activity-based interventions, functional nutrition, and nutraceutical development for the prevention and complementary therapy of noncommunicable chronic diseases. Member of several national and international associations, including the Ibero-American Network for the Integrated Use of Underutilized Indigenous Foods (ALSUB-CYTED) and the National Network for Research, Innovation, and Technological Development in Functional and Nutraceutical Foods (AlFaNutra). https://www. researchgate.net/profile/Abraham_Wall. Francisco J. Olivas-Aguirre, nutritionist (Bachelor) and M.Sc./D.Sc in chemical-biological sciences from the Autonomous University of Ciudad Juarez (Mexico). Research-professor at University of Sonora (Campus Cajeme, Department of Health Sciences; Mexico). His research interests are gastrointestinal nutrition physiology and functional foods for preventing noncommunicable chronic diseases. Member of the National Network for Research, Innovation, and Technological Development in Functional and Nutraceutical Foods (AlFaNutra). https:// www.researchgate.net/profile/Francisco_Olivas-Aguirre. Husain Y. Khan joined Dr. Asfar Azmi’s lab at Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, as a research associate in 2018. Earlier, he was an assistant professor at the Natural and Medical Sciences Research Center, University of Nizwa, Oman. Khan received his Ph.D. in Biochemistry from Aligarh Muslim University, India, in 2013. For his doctoral research at Prof. S.M. Hadi’s lab, he studied the anticancer mechanisms of plant-derived polyphenolic compounds. His work contributed toward the validation of a putative copper-dependent prooxidant DNA breakage mechanism of action of plant polyphenols to explain their anticancer and chemopreventive properties. Khan was awarded a research fellowship by the Council of Scientific and Industrial Research, New Delhi, from 2009 to 2013. His research interests include pancreatic cancer drug discovery, molecular therapeutics, and cancer chemoprevention by natural products. Sheikh Mumtaz Hadi is a professor emeritus in the Department of Biochemistry, Aligarh Muslim University, India. He possesses more than 40 years’ experience in teaching and research in molecular biology. Many of these years were spent in laboratories in the United States, Switzerland, and the United Kingdom. In Switzerland, he worked in the laboratory

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Author biographies

of Nobel Laureate Prof. W. Arber at the University of Basel. His research was mainly focused on the areas of structure and function of nucleic acids. Hadi contributed significantly to DNA repair enzymology, DNA restriction and modification enzymes, and anticancer mechanisms. For the past two decades, he has been interested in plant natural product-mediated chemopreventive mechanisms against cancer. Hadi proposed that plant-derived polyphenols mobilize endogenous copper ions, leading to a prooxidant cytotoxic action against cancer cells. Over the years, he has published several important articles to successfully validate his hypothesis. He received the Elsevier Highest Cited Author Award from Seminars in Cancer Biology for one of his articles published in 2007. Ramzi M. Mohammad is a professor in the Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States. He has more than 25 years of cancer research experience, including extensive experience in molecular biology, animal models, and tissue cultures. He has established a number of pancreatic cancer and other hematological malignancy cell lines and was among the first to establish pancreatic orthotopic models, in which he has years of experience in studying the effects of new anticancer agents, marine products, and standard chemotherapeutic drugs. Mohammad’s research is translational in nature and through his close work with clinicians, he was able to introduce several experimental drugs into the clinic, including Bryostatin-1, Aurastatin-PE, Dolastatin-10, and CA-4 (cambertastatin-4) as well as other small molecule inhibitors of Bcl-2 such as AT-101 (gossypol) and HMD2. Mohammad is currently involved in gastrointestinal cancer research and works in close association with GI physicians at KCI. Asfar S. Azmi is an assistant professor in the Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States. He has more than a decade of experience in the area of small molecule drug development against important cancer targets such as Bcl-2, Mcl-1, nuclear exporter protein CRM1, and p21 activated kinase 4 (PAK4). Azmi’s work has led to the clinical translation of a number of cancer drugs such as the CRM1 inhibitor Selinexor and recently the PAK4 inhibitor KPT-9274. He has published more than 100 peer-reviewed articles and numerous thematic volumes in the area of cancer drug discovery. He is the author of multiple cancer drug discovery books and is also the editor in chief of the Journal Oncobiology and Targets. He has received numerous young investigator awards from premier scientific bodies such as the American Association for Cancer Research and the American Pancreatic Association. His lab is well funded by the National Cancer Institute, the National Institute of Health, and the pharmaceutical industry. Md. Atiar Rahman has been working as an associate professor in the Department of Biochemistry and Molecular Biology at the University of Chittagong, Bangladesh. Rahman was born in 1975 in Jessore, a Southwestern district of Bangladesh. Rahman earned his B.Sc. honors and M.Sc. in biochemistry from the University of Dhaka (Bangladesh) in 1996 and 1997, respectively, securing first class in both exams. He completed his Ph.D. from the United Graduate School of Agricultural Sciences, Ehime University Japan under

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the Japanese Government’s Monbukagakusho Scholarship for 2003–2006. He was also awarded a postdoctoral fellowship at KwaZulu Natal University (Westville Campus) Durban from the National Research Fund of the South African Government. He started his carrier as a lecturer in the Department of Biochemistry and Molecular Biology of the above-mentioned University in 2004 and was promoted to his current position in 2013. He is a principal investigator of the Laboratory of Phytomedicine and Natural Product Research of the aforementioned department. Currently, he is carrying out research to explore novel and indigenous sources of phytomedicinal components as alternative therapeutics and their delivery to cellular targets with convenient vehicles using nanosystems. He has special interests in the discovery and delivery of novel plant-derived drugs as functional foods for noncommunicable chronic diseases, especially type 2 diabetes, and chemically induced acute hepatic toxicity through intervention in animal models. He is working on the phytopharmacological and biological effects of Bangladeshi medicinal plants/plant parts yet to be unveiled, which are being mechanistically justified through simulation using an in silico model. He has been awarded numerous national and international research grants. Right now, he is supervising two Ph.D., five M. Phil, six MS, and three undergraduate students in his lab. He is a life member of many prestigious societies such as the American Society for Microbiology, the Japan Wood Research Society, etc. Rahman has published more than 70 scientific articles, both in national and international peer-reviewed journals. He is also working as an editorial board member of many reputed journals such as BMC Complementary and Alternative Medicine, MedOne, the Indian Journal of Nutrition, and the Asian Journal of Pharmacognosy. He has presented several of his scientific works at home and aboard. He has been awarded the Young Scientist award, the Biosafety award in 2017, etc. Md. Rakibul Hassan Bulbul completed his B.Sc. (2013) and MS (2014) in Biochemistry and Molecular Biology from the University of Chittagong (CU). He is currently working as a research officer at the Institute for Developing Science and Health Initiatives (www.ideshi.org), where he is involved in several projects, including the detection of mycobacterium tuberculosis, the detection of respiratory and enteric pathogens and a pneumonia study among Rohingyas refugees, and the detections of malarial parasites as well as the zika, chikungunya, and dengue viruses in hospitalized patients. During his MS program, Bulbul’s interest in drug discovery from natural resources led him to conduct his thesis under Dr. Md. Atiar Rahman in his Laboratory of Alternative Medicine and Natural Product Research (www.am-npr.com) in Biochemistry and Molecular Biology from the University of Chittagong (CU). He was named a National Science and Technology fellow under the Ministry of Science and Technology in 2015–2016. He is also passionate in his research in cancer biology, epigenetics, the molecular basis of immunological responses, and the host-defense mechanism. Bulbul has professional collaborations with the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR), the Banrieux Foundation gladesh Institute of Tropical and Infectious Diseases (BITID), and the Me

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Author biographies

(France). He is also a member of the Graduate Biochemists Association (GBA) and the Chittagong University Biochemistry and Molecular Biology Alumni Association. Peter Kubatka obtained his Sc.D. and Ph.D. (Animal Physiology) from Science Faculty of P.J. Safarik University, Slovak Republic. He is an experimental oncologist at the Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. He graduated in Biology at the University of P.J. Safarik in Kosice, Slovakia (1997). He has a particular interest in experimental breast carcinoma. He evaluated the chemopreventive effectiveness and mechanism of anticancer action of retinoids, nonsteroidal antiinflammatory drugs, selective estrogen receptor modulators, aromatase inhibitors, antidiabetics, statins, different phytosubstances/plant-based functional foods, and melatonin in a mammary carcinoma model. Kubatka has authored or coauthored more than 100 original manuscripts (Scopus, PubMed, or Web of Science). Martin Kello is a researcher in the field of oncology, molecular cytopathology, and pharmacology in the Department of Pharmacology, Medical Faculty of P.J. Safarik University in Kosice, Slovak Republic. He graduated with a Ph.D. in Genetics at the University of P.J. Safarik in Kosice, Slovakia (2010). He has an interest in experimental oncology research. He evaluated mechanisms of potential antiproliferative and anticancer actions of natural and synthetic compounds (polyphenols, flavonoids, acridins, phytoalexins, chalcones, and other) in human carcinoma models. Kello is the author or coauthor of 31 scientific articles (Current Contents database). Alena Liskova is a first-year Ph.D. student at the Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. She holds a master’s degree from Constantine the Philosopher University in Nitra (2018). Her research interest centers on experimental mammary carcinogenesis. In cooperation with her supervisor Dr. Kubatka, she focuses on the chemopreventive efficacy of phytochemicals in animal models. Jan Mojzis is a professor of pharmacology at the Medical Faculty of P.J. Sˇafarik University in Kosˇice, Slovak Republic. He obtained his DVM in 1980 from the University of Veterinary Medicine in Kosˇice and his DSc. in 2012 from P.J. Sˇafarik University in Kosˇice. His research interest is the discovery of novel compounds of natural, semisynthetic, and synthetic origin with anticancer effects. The results of his research have been published in more than 180 scientific journals (Web of Science). Mojzˇisˇ received numerous scientific research grants and has supervised the research work of several Ph.D. students. He is a member of the Committee of the Slovak Pharmacological Society. Peter Solar Sc.D., Ph.D., is an associate professor at the Department of Medical Biology, Faculty of Medicine, Pavol Jozef Sˇafa´rik University in Kosˇice, Slovak Republic. He graduated in biology at the Faculty of Science, Pavol Jozef Sˇafa´rik University in Kosˇice. He has a particular interest in the resistance of cancer cells to different therapies. He is evaluating the role of the erythropoietin receptor in the proliferation and progression of human ovarian and breast cancer cells. Sola´r has authored or coauthored more than 60 original manuscripts (Scopus, PubMed, or Web of Science).

Author biographies

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Zuzana Solarova, M.D., Ph.D., is an assistant professor at the Institute of Pharmacology, Faculty of Medicine, Pavol Jozef Sˇafa´rik University in Kosˇice, Slovak Republic. She graduated in general medicine at the University of P.J. Sˇafa´rik in Kosˇice (1998), Slovakia. She has a particular interest in the study and experimental testing of new potential anticancer drugs from naturally occurring substances as well as heat shock protein inhibitors. Sola´rova´ has authored or coauthored more than 10 original manuscripts (Scopus, PubMed, or Web of Science). Pavol Zubor M.D., Ph.D., DSc., MBA, FRSM, is the head of the Clinic of Gynecology and Obstetrics at Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. He graduated in General Medicine at Jessenius Faculty of Medicine (2001). His work centers on malignant diseases of the female genitalia and breast and the introduction of new diagnostic methods and surgical procedures. His scientific interest focuses mainly on applied and translational research dealing with uterine, ovarian, and breast cancer in women as well as the biological profile of the disease and the consequent surgical or adjuvant treatment. He has published more than 110 articles. Anthony Zulli is an academic scientist at Victoria University, Melbourne, Australia. He obtained his Ph.D. at the University of Melbourne in 2003 and since then has been focusing on the links between atherogenesis and cancerogenesis, with specific interest in the role of the renin angiotensin system, the nitric oxide system, and the cell stress systems in cell growth. He has authored or coauthored more than 80 publications (PubMed). Jan Danko M.D., Ph.D., is a deputy head of the Clinic of Gynecology and Obstetrics at the Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. He graduated in General Medicine at the Jessenius Faculty of Medicine in Martin (1975), Slovakia. He worked as a multiannual head of the Clinic of Gynecology and Obstetrics (1991–2018) and dean of the Jessenius Faculty of Medicine (2000–2007 and 2011– 2018). He has authored or coauthored 118 scientific articles (Scopus). Norhafiza Mat Lazim is a consultant otorhinolaryngologist at Hospital Universiti Sains Malaysia. She obtained her MBBS from the University of Queensland, Australia, in 1999. She completed her Master of Medicine in Otorhinolaryngology-Head and Neck Surgery from Universiti Sains Malaysia in 2012. Subsequently, she obtained her Clinical Fellowship in Head and Neck Surgical Oncology from Antoni van LeeuwenhoekNetherland Cancer Institute (AVL-NKI), Amsterdam, Netherlands, in 2014 and from VUMC, Free University Hospital, Amsterdam, in 2015. She has a strong interest in head and neck surgery and head and neck oncology. She has acquired several short-term and university research grants on head and neck diseases and tumors. She is one of the coresearchers for a multicenter clinical trial on carcinoma of the tongue that is based in the United States. She has a total of 40 publications in peer-reviewed journals as well as several book chapters. She is a reviewer for multiple international journals as well as serves as an editorial board member to numerous international journals. She has presented both in oral and poster presentations internationally and locally. She is a member of the American Head and Neck Society (AHNS), the European Head and Neck Society

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Author biographies

(EHNS), the Asian Head and Neck Oncology (ASHNO), the American Thyroid Association (ATA), and the British Association of Head and Neck Oncology (BAHNO). She is currently an honorary secretary of the Malaysia Society of Otorhinolaryngology-Head and Neck Surgery (MSOHNS). She has actively organized community-based events, especially in relation to promoting awareness of head and neck cancer and healthy lifestyles. In Sil Park is a Ph.D. candidate in Agricultural Biotechnology at Seoul National University. Her research interest is the impact of phytoceuticals from natural plants in visceral obesity using human adipose-derived stem cells. She obtained her B.Sc. and M.Sc. in Agricultural Biotechnology at Kyungpook National University in 2010 and 2013, respectively. Also, she worked as a researcher at the Korea Institute of Oriental Medicine from 2013 to 2016. Jae Hyun Cho is currently an assistant professor in the Department of Obstetrics and Gynecology at Soon Chun Hyang University Hospital Seoul, Republic of Korea. He received his M.D. from the Inje University College of Medicine in 2009 and his masters of science at the University of Ulsan College of Medicine in 2014. Cho trained at the Asan Medical Center in Seoul at the Department of Obstetrics and Gynecology during his residency. Afterward, he completed a fellowship in Gynecologic Oncology at Seoul National University College of Medicine. Youngjin Han is a fourth year Ph.D. student majoring in Biomodulation in the Department of Agricultural Biotechnology, Seoul National University, and a graduate studentresearcher at the Cancer Research Institute, Seoul National University. His doctoral research investigates the impact of the tumor microenvironment on mitochondrial dynamics in cancer cells. Specifically, his main focus is on tumor microenvironmental factors associated with cancer progression. He holds a bachelor’s degree in Arts and Science from the University of Toronto, Canada. He double-majored in Neuroscience and Cell and Molecular biology during his undergraduate study. Ki Won Lee received his Ph.D. in Agricultural Biotechnology at Seoul National University (SNU) in 2004. After finishing his postdoctoral training with Prof. Zigang Dong at the University of Minnesota, he started his academic carrier as an assistant professor in the Department of Bioscience and Biotechnology at Konkuk University in 2006. Currently, he is a professor in the Department of Agricultural Biotechnology and the director of the XO Center (Wellness Emergence Center) at the Advanced Institutes of Convergence Technology at SNU. His research interests are in the areas of convergence technology. Principally, his current research focuses on the development of disease-targeting phytoceuticals and personalized wellness care systems utilizing convergence technologies. Yong Sang Song is currently a professor at Seoul National University, College of Medicine. He received his medical doctor’s degree and Ph.D. at Seoul National University, Korea, in 1983 and 1994, respectively. He worked at the University of Wyoming, Laramie, as a research fellow in the Department of Molecular Biology from 1997 to 1999. He served as an associate professor at Seoul National University from 2001 to 2005. He has served

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as a professor and the associate dean of Research Associate from 2006 to 2008, and director of the Cancer Research Institute at Seoul National University from 2009 to 2015. He was elected as president of the Korean Society of Urogynecology in 2006 and Cancer Prevention in 2012. In 2009, he organized the International Conference of NAPA and was elected as the chairperson of the Asian Society of Gynecologic Oncology (ASGO) Scientific Committee. He served as the president of the International Society of Precision Medicine (ISPCM) in 2018 and 2019. His major research interests are molecular mechanisms of tumors, especially the role of tumor microenvironment in cancer cell metabolism, chemoresistance, and precision medicine in gynecologic cancer. He is particularly interested in the impact of components of tumor microenvironments in ovarian cancer progression. He has published more than 300 papers in the science citation index (SCI) journals such as NEJM, Lancet oncology, Cancer Research, Molecular Carcinogenesis, Cancer Letters, Scientific Reports, and Oncogene. He has received numerous awards, including the prize of the Scientific Paper (Korean Scientific Association), the grand prize (Korean Society of Colposcopy and Gynecologic Oncology), an academic award (International Conference on Ovarian Cancer), the President Award on Prevention (Korean Government), the Boryung Cancer Academic Award on Prevention (Korea), and the award of the 16th health/medical technology development (minister of health and welfare). He is also the editor in chief, senior editor, and member of the editorial board of several scientific journals such as International Journal of Clinical Medicine, Journal of Cancer Prevention, Cancer Letters, Scientific Reports, Frontier in Oncology, JTCM, Molecular Carcinogenesis, etc. Maria Gabriela Valle Gottlieb graduated in Biological Sciences, master and Ph.D. in Health Sciences at the Pontifical Catholic University of Rio Grande do Sul. Postdoctoral degree in Biomedical Gerontology by the Graduate Program in Biomedical Gerontology of the Medical School of the Pontifical Catholic University of Rio Grande do Sul (PUCRS). Investigates the following topics: aging process, gene-environmental interaction, ecology and diseases, microbiota, and lifestyles. Biogerontologist. Postdoctoral Researcher in Aging Process and Life Style. Professor and researcher at the Biomedical Gerontology Graduate Program of the School of Medicine and Institute of Geriatrics and Gerontology of the Pontifical Catholic University of Rio Grande do Sul (IGG-PUCRS). Vilma Maria Junges graduated in Nutrition at the Centro Universita´rio Metodista. Specialist in clinical nutrition by the Methodist University Center. Specialist in obesity and weight loss at Universidade Gama Filho. Master in Biomedical Gerontology by the Graduate Program in Biomedical Gerontology of the Medical School of the Pontifical Catholic University of Rio Grande do Sul (PUCRS). Researcher at the Integrated Center for Obesity Treatment (CINTRO). Investigates the following topics: obesity, bariatric surgeries, nutritional assessment, anthropometry, and metabolic syndrome. Nutritionist at the Integrated Center for Obesity Treatment (CINTRO). Vera Elizabeth Closs graduated in Nutrition, masters and Ph.D. in Biomedical Gerontology by the Graduate Program in Biomedical Gerontology of the Medical School of the

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Author biographies

Pontifical Catholic University of Rio Grande do Sul (PUCRS). Scientific coordinator of the Group of Interest in Nutrition of the Brazilian Society of Geriatrics and Gerontology Section Rio Grande do Sul. Investigates the following topics: scientific research methodology, nutritional assessment, anthropometry, fragility syndrome, sarcopenia, and metabolic syndrome. Researcher at the Geriatrics and Gerontology Institute’s Cardiometabolic Risk, Aging, and Nutrition Study Group (GERICEN) at Pontifı´cia Universidade Cato´lica do Rio Grande do Sul (PUCRS). Raquel Seibel graduated in Nutrition at the Universidade de Cruz Alta (UNICRUZ). Master in Biomedical Gerontology and Ph.D. student in Biomedical Gerontology at the Graduate Program in Biomedical Gerontology of the Medical School of the Pontifical Catholic University of Rio Grande do Sul (PUCRS). Specialist in Clinical Nutrition by the University of Vale do Rio dos Sinos (UNISINOS). Participates in the Group of Interest in Nutrition of the Brazilian Society of Geriatrics and Gerontology Section Rio Grande do Sul Investigates the following topics: nutrition, aging, and gerontology. Atiqur Rahman has obtained his M.Sc. (Biochemistry and Molecular Biology) and Ph.D. (Inflammation Biology) degree from University of Dhaka, Bangladesh and University of Sheffield, UK, respectively. He is currently serving as an associate professor at the Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh. His current research focuses on studying molecular mechanisms of neutrophilic inflammation in the context of inflammatory diseases, including cancers. Sajib Chakraborty has obtained his M.Sc. (Molecular Medicine) and Ph.D. (Proteomics and Systems Biology) degree from University College London, UK and German Cancer Research Center (DKFZ), Heidelberg, Germany, respectively. He is currently serving as an associate professor at the Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh. His current research topics are but not limited to: Integration of multi-OMICS data to investigate the concordance and discordance between transcription and translational process in diverse cell/tissues of mammalian system including: cancer tissues and hematopoietic stem cells. Yearul Kabir graduated in Biochemistry from University of Dhaka (Bangladesh) in 1983 and obtained Ph.D. in Nutritional Biochemistry from Tohoku University (Japan) in 1990. Kabir joined as lecturer in the Department of Biochemistry (now Department of Biochemistry and Molecular Biology), University of Dhaka in 1984 and became professor in the same department in 1997. Throughout his long 35 years of teaching and research career, Kabir worked on various aspects of human nutrition and molecular genetics of cancer. His research interests include but are not limited to cancer and metabolic disorders. He has supervised four Ph.D. students by research and currently supervising seven Ph.D. students, three of whom are nearing completion. He has published more than 100 research papers in reputed national/international peer-reviewed journals as well as 11 chapters in books published from United States. He has presented several of his scientific works at home and aboard. He has been awarded numerous national and international research grants.

Author biographies

xxxiii

He is a reviewer for multiple international journals such as Scientific Reports, Tumor Biology, Oncology Letter, Cancer Epidemiology, Clinical and Experimental Pharmacology and Physiology, Nutrition Research, Public Health Nutrition, BMC Complementary and Alternative Medicine, Frontiers in Public Health Section Environmental Health, etc. as well as serves as an editorial board member to various international journals. Kabir worked as a visiting scientist at the National Institute of Environment Studies, Japan (1993), as UNU-fellow at the National Food Research Institute, Japan (1994– 1995), as research fellow in the Laboratory of Nutrition, Tohoku University, Japan (1995–1996), as visiting scientist at the Institute of Nutritional Physiology, Federal Research Centre for Nutrition, Germany (1998–1999), as JSPS-fellow in the Laboratory of Nutrition, Tohoku University, Japan (2003–2004), and as JSPS-Bridge fellow in the Laboratory of Nutrition, Tohoku University, Japan (2012). He also worked as an associate professor in the Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait (2004–2009). Besides his academic and administrative involvement with the University of Dhaka, he is also associated with many other universities, academic Institutes/organizations and Professional Societies. He is a Fellow of Bangladesh Academy of Sciences (BAS). Towfida Jahan Siddiqua obtained her M.S. and Ph.D. (Nutritional Biology) from the University of California, Davis. She is currently an assistant scientist at the International Centre for Diarrhoeal Disease Research, Bangladesh. As one of five female scientists from the developing world, she received the "Gro Brundtland Award 2016" for her academic performance and investment in the field of sustainable development and public health nutrition. Siddiqua received her B.S. and M.S. in biochemistry and molecular biology from the University of Dhaka, Bangladesh. She was awarded an NIH Fogarty scholarship to study in the program in Community and International Nutrition, University of California, Davis. Thereafter, she completed the prestigious GloCal Health Fellowship (postdoctoral) supported by the NIH Fogarty International Center. Siddiqua’s areas of specialization include maternal and child nutrition, micronutrient deficiencies in developing countries, epigenetics, and the relationship between nutrition and infection. She has been a member of the International Society for Research in Human Milk and Lactation (ISRML) since 2018, and also an associate member of the American Society for Nutrition since 2017. S.M. Rafiqul Islam started his postdoctoral fellowship training in February 2016 at the Surgery Branch, National Cancer Institute (NCI), National Institute of Health, Bethesda, Maryland, United States. Before starting his postdoctoral training at NCI, he obtained his Ph.D. in medicine from the Chiba University School of Medicine, Chiba, Japan, in 2014. His major focus in his Ph.D. work was identifying molecular mechanisms of a de novo gene that promote the gene function of the oncogene MYCN and contribute to aggressive forms of metastasis in childhood brain cancers such as neuroblastoma, glioblastoma, and pineocytoma. In addition, he also focused on making a model system to examine the characteristics of neuroblastoma cancer stem-like cells (CSC) that initiate and progress cancers and screening a small molecule compound as a chemotherapeutic

xxxiv

Author biographies

agent in neuroblastoma. Before starting his Ph.D. journey, he completed his B.Sc. and MS from the Department of Biochemistry and Molecular Biology at the University of Dhaka, Bangladesh, in 2008. Going further back, he was born and grew up in Pabna and Rajshahi in the northeastern part of Bangladesh, where he finished his school and college. Rakesh Sharma has a Ph.D. in Biochemistry and a second Ph.D. in Magnetic Resonance Imaging from the Indian Institute of Technology, New Delhi. Currently, he is professor at AMET University and the Saraswathi Institute of Medical Sciences, Hapur. He taught as an associate professor at Florida State University. He is an affiliate scientist at Columbia University, New York. He has 125 research papers and 3 books edited on enzyme inhibition and stem cell therapy. Robert Moffatt has a Ph.D. in Nutrition and Food Science with an M.P.H. from Ann Arbor, Michigan. He has served as a senior professor at Florida State University since 1989. He has 141 research publications in the field of exercise physiology.

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Natural remedies and functional foods as angiogenesis modulators Mehmet Varol DE PARTMENT OF MO LECULAR BIOLOGY AND GENE TIC S, F AC UL TY OF SCIE NCE, KO T EKL I CAMPUS, MUGLA SITKI K OCMAN UNIVERSITY, MUGLA, TURKEY

Angiogenesis definition and background Vertebrate cells need an appropriate microenvironment surrounded by blood capillaries to ensure maintaining their normal functions and the convenient microenvironment that formed a balanced composition of oxygen and nutrient substances, and metabolic wastes resulting from the vital activities of the cells is ensured by the cardiovascular or circulatory system (Pittman, 2013). The system is established via two mechanisms: vasculogenesis and angiogenesis. Both these mechanisms are essential for the formation of a vascular network in the early stages of embryonic development as well as in the rest of the lifespan (Drake, 2003). Although angiogenesis is defined as a complex process of expansion and remodeling of a preexisting vascular structure, vasculogenesis refers to the de novo blood vessel constitution accomplished by the de novo generation of endothelial cells, which includes a series of differentiation processes from mesodermal progenitors into angioblasts and then from angioblasts into endothelial cells (Patan, 2004; Risau and Flamme, 1995). In normal physiology, angiogenesis has a major role in tissue growth, healing, reproduction, and development of the fetus during pregnancy (Felmeden et al., 2003). All cells in the body desperately need oxygen to maintain their vital activities within homeostasis and the diffusion distance of oxygen within the tissues is restricted to 100–200 μm (Grimes et al., 2014; Varol, 2017). When a cell stays away from the capillary blood vessels farther than the appropriate diffusion distance of oxygen, it is inevitable that physiological stresses such as hypoxia along with starvation and acidification occur within the cell (Wenger et al., 2015; Carmeliet and Jain, 2000). Therefore, a cell that is deprived of oxygen can release proangiogenic growth factors, along with other positive regulation proteins such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), fibroblast growth factor (FGF), epidermal growth factor (EGF), matrix metalloproteinase (MMP) enzymes, angiopoietins, and integrin proteins to initiate the formation of the surrounding blood capillaries (Weis and Cheresh, 2011; Salajegheh, 2016; Carmeliet, 2005). There are also angiogenesis suppression (antiangiogenic) factors such as angiopoietin-2, platelet factor-4, thrombospondin-1 and -2, endostatin, angiostatin, Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00001-6 © 2020 Elsevier Inc. All rights reserved.

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Functional Foods in Cancer Prevention and Therapy

osteopontin, collagen, kininogens, and the tissue factor pathway inhibitor (TFPI) as well as angiogenesis-inducing (angiogenic) factors in the body (Ribatti, 2009; Mousa and Davis, 2017). The regulation of the balance between angiogenesis activators and inhibitors in the body provides an angiogenic switch that affects the formation of capillaries, and the direction in which the balance between these factors in the microenvironment is dominant regulates the opening and closing of the angiogenic switch (Varol, 2017; Carmeliet, 2005; Hanahan and Weinberg, 2011; Bouck et al., 1996; Hicklin and Ellis, 2005). Briefly, if the amount of the antiangiogenic factors is greater than the amount of the angiogenic factors, the angiogenic switch is closed and the existing blood vessels begin to decompose or no change occurs in their structures. In other words, if the amount of the angiogenic factors in the microenvironment is greater than the amount of the antiangiogenic factors, the angiogenic switch is opened and the constitution of new capillaries from existing blood vessels is triggered (Varol, 2017; Carmeliet, 2005; Ribatti, 2009). During the menstrual cycle in a healthy woman, for example, the development of the endometrium leads to opening the angiogenic switch and the formation of highly developed vascularity, although shedding of the endometrium leads to the degradation of the surrounding blood vessels, which then again undergo angiogenesis for the renovation of the endometrium (Smith, 2001; Folkman, 2006). It is widely known that mutual communication between the adjacent cells and their microenvironment plays an important role in the regulation of the angiogenic switch as well as the regulation of tissue shrinkage and destruction or tissue growth and development (Carmeliet and Jain, 2000; Ribatti, 2009; Quail and Joyce, 2013). Many changes in the microenvironment can have an important role in the determination of the fate of the angiogenic switch due to the mutual communication between the cells or the some genetic mutation (Varol, 2017; Carmeliet and Jain, 2000; Kerbel, 2000). These factors include mechanical stress depending on the proliferation and growing rates of cells in a tissue, the presence of metabolic stress factors such as low glucose level (hypoglycemia), a low pH level (acidification) due to metabolic waste accumulation because of aggressive metabolic activity, iron deficiency (hypoferremia), deprivation of oxygen (hypoxia), the infiltration of cells related to the immune and inflammatory systems into the tissues, and the rearrangement of the metabolic pathways. After the angiogenic switch is opened, a series of cellular processes is operated under the control of cells, soluble factors, and extracellular matrix components (Salajegheh, 2016). Two types of angiogenesis, called sprouting angiogenesis and intussusceptive angiogenesis, can be observed both in utero and in adults (Burri and Tarek, 1990; Caduff et al., 1986). There is limited information in the literature about the intussusceptive angiogenesis compared to sprouting angiogenesis, which was reported for the first time by Ausprunk and Folkman (1977). Ausprunk and Folkman (1977) reported that sprouting angiogenesis can initially progress without cell division, although proliferation is essential for sustained sprouting and further outgrowth. Sprouting angiogenesis is especially induced by the cells that have a hypoxic condition in their microenvironment due to poor tissue perfusion. These cells initiate a series of processes that can be listed as the enzymatic degradation of the capillary basement membrane at the localization of the angiogenic stimulus, the debilitation of the

Chapter 1 • Natural remedies and functional foods

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contacts between endothelial cells, the proliferation of endothelial cells and their migration in a directed way to connective tissue, the formation of capillary-like structures (tubulogenesis), the anastomosis of the new tubular sprouts (vessel fusion), the synthetization of the new basement membrane, and the stabilization of pericytes (Ausprunk and Folkman, 1977; Ribatti and Crivellato, 2012; Adair and Montani, 2010). On the other hand, the word “intussusception” means growth within itself and intussusceptive angiogenesis, defined as capillary vessel growth within itself, is briefly carried out by an extension of the vessel wall into the lumen, causing a single vessel to split in two (Djonov et al., 2000; Burri et al., 2004). As an alternative to sprouting angiogenesis, intussusceptive angiogenesis has an important role in the formation of a vascular system in embryos where growth is rapid and resources are limited, although it can be observed throughout life (Burri et al., 2004; Djonov et al., 2003). In intussusceptive angiogenesis, there is no need for immediate endothelial cell proliferation, extensive migration, basement membrane degradation, or invasion of the surrounding tissue because it is a rapid and efficient process in a metabolically and energetically more economic manner, and only requires reorganization of existing endothelial cells that thereby form less leaky capillaries (Kurz et al., 2003). Intussusceptive angiogenesis, also called splitting angiogenesis, occurs by the processes that can be listed as capillary plexus expansion that provides a broad endothelial surface for metabolic exchange; the formation of changes in the position, form, and size of the perfused capillary segments as a result of the arborization and the creation of a hierarchical tree; and the modification and optimization of the supplying vessel branching geometry and flow property by remodeling the branches, which includes not only the formation of new branches but also the removal of existing ones as a response to the alterations in metabolic requirements (Djonov et al., 2003; Kurz et al., 2003).

Molecular mechanism of angiogenesis As previously mentioned, angiogenesis has emerged as a sophisticated molecular phenomenon that includes a complex balance between the amount of angiogenic and antiangiogenic factors, which determines the fate of the angiogenic switch and thereby the formation, modification, stabilization, or degradation of the existing capillary vessels (Varol, 2017; Carmeliet, 2005; Hanahan and Weinberg, 2011; Bouck et al., 1996; Hicklin and Ellis, 2005). Therefore, many molecular signaling pathways include proangiogenic and antiangiogenic factors that are given in Table 1.1 and Table 1.2 (Carmeliet and Jain, 2000; Carmeliet, 2005; Kumar et al., 2016). As can be seen in Tables 1.1 and 1.2, the majority of the angiogenesis activators and inhibitors are growth factors such as hepatocyte growth factors (HGF), transforming growth factors (TGF), platelet-derived growth factors (PDGFs), and vascular endothelial growth factors (VEGFs); the other factors generally take a complementary role in the angiogenic and antiangiogenic pathways (Kumar et al., 2016). Endogenous antiangiogenic factors usually work as inhibitors of the components of the capillary vessels or endogenous angiogenic factors (Carmeliet and Jain, 2000). Vascular endothelial growth factor (VEGF) family members, for instance, play an important role

Table 1.1

Angiogenic factors.

Angiogenic factors

References

Vascular endothelial growth factor (VEGF) family members Neuropilin-1 (NRP-1) Angiopoietin 1 (Ang1) and Ang1 receptor (Tie2) Platelet-derived growth factor-BB (PDGF-BB) and receptors Fibroblast growth factor (FGF) Hepatocyte growth factor (HGF) Monocyte chemoattractant protein-1 (MCP-1) Nitric oxide synthase (NOS) Cyclooxygenase-2 (COX-2) Inhibitor of differentiation 1 (Id1) and Id3 Vascular endothelial cadherin Platelet endothelial cell adhesion molecule (PECAM-1 or CD31) Plasminogen activators and matrix metalloproteinases (MMPs) Plasminogen activator inhibitor-1 (PAI-1) Transforming growth factor beta-1 (TGF-β1), TGF-β receptors Prominin-1 (AC133 or CD133) Integrins αvβ3, αvβ5, α5β1 Chemokines Ephrins Leptin Endoglin

Holmes and Zachary (2005) Parikh et al. (2004) Suri et al. (1996) Saik et al. (2011), Marx et al. (1994) Presta et al. (2005) Xin et al. (2001) Hong et al. (2005) Murohara et al. (1998) Gately (2000) Lyden et al. (1999) Gory-Faure et al. (1999) Horak et al. (1992) Mignatti and Rifkin (1996) McMahon et al. (2001) Pepper (1997) Fargeas (2006) Kim et al. (2000) Strieter et al. (2004) Cheng et al. (2002) Bouloumie et al. (1998) Ten Dijke et al. (2008)

Table 1.2

Antiangiogenic factors.

Antiangiogenic factors

References

VEGFR-1; soluble VEGFR-1 Soluble NRP-1 Angiopoietin 2 (Ang2) Thrombospondin-1 (TSP-1), TSP-2 Angiostatin and related plasminogen kringles Prothrombin kringle-2; antithrombin III fragment Fragment of SPARC Osteopontin fragment Prolactin Canstatin Vascular endothelial growth inhibitor (VEGI) Platelet factor-4 Maspin MMP inhibitors Meth-1; Meth-2 Proliferin and proliferin-related protein Restin IFN-α, -β, -γ; IP-10, IL-4, IL-12, IL-18

Shibuya (2006) Geretti and Klagsbrun (2007) Lobov et al. (2002) Tolsma et al. (1993) Tarui et al. (2002) Kim et al. (2002)

Retinoids Vasostatin Calreticulin Endostatin (collagen XVIII fragment)

Jendraschak and Sage (1996) Hirama et al. (2003) Ueda et al. (2006) Kamphaus et al. (2000) Zhai et al. (1999) Bikfalvi (2004) Zhang et al. (2000) Raza and Cornelius (2000) Va´zquez et al. (1999) Jackson et al. (1994) Ramchandran et al. (1999) Voest et al. (1995), Cao et al. (1999), Volpert et al. (1998), Strieter et al. (1995), Jablonska et al. (2010), Beatty and Paterson (2001) Majewski et al. (1993) Pike et al. (1998) Pike et al. (1999) O’Reilly et al. (1997)

Chapter 1 • Natural remedies and functional foods

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through a family of cognate receptor kinases in endothelial cells to stimulate angiogenesis and vasculogenesis, although vascular endothelial growth factor receptor-1 (VEGFR-1), soluble VEGFR-1, platelet factor-4, prolactin, and the fragment of the matricellular protein SPARC (secreted protein acidic and rich in cysteine) act as the inhibitors of VEGF (Carmeliet and Jain, 2000; Kumar et al., 2016; Holmes and Zachary, 2005). Although neuropilin-1 (NRP-1) integrates the survival and angiogenic signals, the soluble isoform of NRP-1 inhibits VEGF, VEGF-B, and PIGF (placental growth factor), which are members of the VEGF family (Schuch et al., 2002; Olofsson et al., 1998; Zhang et al., 2009). Angiopoietin-1 contributes to the formation of capillary vessels by playing a substantial role in the vessel remodeling, maturation, and stabilization or inhibiting permeability, whereas angiopoietin-2 acts as the antagonist of angiopoietin-1 (Stratmann et al., 1998). On the other hand, there are some antiangiogenic factors such as prothrombin kringle-2, antithrombin III fragment, trombospondins (TSP-1 and TSP-2), endostatin, vasostatin, calreticulin, interferons (IFN-α, IFN-β and IFN-γ), interferon gamma-induced protein 10, and interleukins (IL-4, IL-12 and IL-18) that are directly active on endothelial cell growth, survival, adhesion, and migration (Carmeliet and Jain, 2000; Lee et al., 1998; Lawler, 2002; Coughlin et al., 1998). Understanding the molecular mechanisms of angiogenesis is of great importance to search for new treatment opportunities to cure angiogenesis-dependent diseases such as ocular fundus diseases, neurodegenerative diseases, rheumatoid arthritis, diabetic retinopathy, endometriosis, atherosclerosis, psoriasis, osteoporosis, diabetes, and cancer (Salajegheh, 2016; Lopes et al., 2013).

Screening methods of angiogenesis modulators Screening functional foods and natural remedies for vasculogenesis and angiogenesis stimulation, inhibition, and the related-signal transduction targeting activities requires in vitro and in vivo assay systems for molecular target identification and validation, and optimization of dose scheduling and a convenient drug combination strategy (Losso, 2007). Researchers expect that an ideal angiogenesis or vasculogenesis assay should be easy, quantitative, reproducible, cost-effective, and rapid, although each assay has limitations (Mousa et al., 2017). The most common in vitro and in vivo angiogenesis assays can be seen in Table 1.3.

Natural angiogenesis modulators In this part of the chapter, the traditional natural formulations as well as plant and mushroom sources are summarized and put together in Table 1.4, and the natural products that take a role in the modulation of angiogenesis are listed in Table 1.5. It is widely acknowledged that medicinal plants, mushrooms, and herbs are the lead and key sources for human welfare because the relationship between mankind and natural cures is as old as the existence of humankind, and unnatural treatment strategies can cause some

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Table 1.3 Assay system

The most common in vivo and in vitro angiogenesis assays. Experimental model

Proliferation MTT Assay

Proliferation XTT Assay

Proliferation WST-1 Assay

Proliferation LDH Assay

Proliferation AlamarBlue Assay

Proliferation BrdU Assay

Proliferation EdU Assay

Proliferation Trypan Blue

Proliferation PicoGreen Proliferation Ki67

Proliferation CFSE Proliferation Live/Dead Assays

Proliferation Real-Time Cytotoxicity Assays Migration

Boyden Chamber Assay

Specifications

References for assay protocol

Measures living cells using spectrophotometer, is fast and has high throughput, but an endpoint assay Measures living cells using spectrophotometer, is water soluble and highly sensitive, but an endpoint assay Measures living cells using spectrophotometer, is fast and highly sensitive, but an endpoint assay Measures dead and dying cells, is fast and has high throughput, but an expensive and endpoint assay Measures living cells using spectrophotometer, is fast and highly sensitive, but an endpoint assay Measures DNA replication, is precise, fast, and nonradioactive, but has a lengthy protocol and DNA damage risk Measures DNA replication, is less toxic than BrdU assay, and does not need DNA denaturation, but has expensive reagents Measures dead and dying cells using microscopy, is low cost and rapid, but variable and inaccurate Measures dsDNA amount, is rapid and highly sensitive, but expensive Measures cellular proliferation, is convenient for in vivo application, but requires fixation Measures living cells, is a live cell analysis, but has a toxic effect Measures viable and dead cells, is a live and single cell analysis and rapid, but has some inaccurate results Measure viable and/or dead cells, gives real-time results, but is expensive and needs developed equipment Measures migrated cells, is sensitive, fast, and cost-effective, but timeconsuming and technically difficult to set up

van Meerloo et al. (2011)

Roehm et al. (1991)

Peskin and Winterbourn (2000)

Smith et al. (2011), Varol (2018)

Varol (2018), Bonnier et al. (2015)

Darzynkiewicz and Juan (1997)

Salic and Mitchison (2008)

Strober (2015)

Varol (2018) Soares et al. (2010), Key et al. (1994) Quah and Parish (2010) Lorenzo et al. (1994)

Ke et al. (2011)

Chen (2005)

Chapter 1 • Natural remedies and functional foods

Table 1.3

The most common in vivo and in vitro angiogenesis assays—cont’d

Assay system

Experimental model

Migration

Wound Healing Assay

Migration

Migration

Migration

In Vitro

In Vitro

In Vitro

Organ Culture

In Vivo

In Vivo

In Vivo

7

Specifications

Measures migration rate, is convenient, inexpensive, high throughput, and simple, but quantification is somewhat arbitrary Phagokinetic Track Motility Measures total cell motility, needs Assay common laboratory equipment and chemicals, but has a lengthy protocol Teflon Fence Assay Measures migrated cells, is highly sensitive, but technically difficult to set up Real-Time Cellular Migration Measures real-time cellular migration, is Assay highly sensitive and simple, but expensive and needs developed equipment Tube or Cord Formation Measures the formation of tube-like Assay structures, is high throughput, quantifiable, and easy to set up, but dependent on the type of support matrices Sprouting Assay Measures the tubules that form in all three dimensions, closely mimics the in vivo situation, but notoriously difficult to analyze Coculture Assay Measures tubulogenesis that is actualized more closely in the in vivo situation, but time-consuming and technically difficult to set up Whole or partial vessel Measures microvessel outgrowth, is outgrowth assays (from rat, widely used, reproducible, and highly mouse, chick, porcine or sensitive, but technically difficult human) Chorioallantoic Membrane Needs a developing chick embryo, is (CAM) Assay simple, cost-effective, and convenient for large-scale screening, but sensitive to oxygen tension and hard to observe new capillaries due to preexisting vascular network Corneal Pocket Assay Is performed in rabbit, rat, or mice cornea, reliable but expensive, timeconsuming, technically difficult, and ethically questionable Matrigel Plug Assay Is performed in mice and provides a natural environment, but expensive and time-consuming

References for assay protocol Liang et al. (2007)

Nogalski et al. (2012)

Cai et al. (2000)

Bird and Kirstein (2009)

Arnaoutova and Kleinman (2010), Varol et al. (2018)

Janvier et al. (1997)

Bishop et al. (1999), Donovan et al. (2001)

Bellacen and Lewis (2009), Nicosia and Ottinetti (1990), Masson et al. (2002), Chau and Figg (2007) Wilting et al. (1991)

Ziche and Morbidelli (2012), Morbidelli and Ziche (2004)

Coltrini et al. (2013)

Continued

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Functional Foods in Cancer Prevention and Therapy

Table 1.3

The most common in vivo and in vitro angiogenesis assays—cont’d

Assay system

Experimental model

In Vivo

Sponge Implant Model

In Vivo

In Vivo

In Vivo

Specifications

References for assay protocol

Is performed in mice or rats, technically simple and inexpensive, but timeconsuming and has a lengthy protocol Tumor Models Allows a realistic model for human cancers in nude mice, but timeconsuming and technically difficult to set up Dorsal Air Sac Assay (DASA) Is performed in a dorsal air sac under the skin of mice, technically simple, but invasive and hard to observe new capillaries due to preexisting vascular network Zebrafish Models Is fast, quantitative, and convenient, but expensive and has some technical problems

Table 1.4

Andrade and Ferreira (2009)

Hoffman (2005)

Seon (2015)

Ali et al. (2015)

Antiangiogenic functional foods and natural remedies.

Natural sources

Findings

Mechanisms

References

Allium ascalonicum Aloe vera

Inhibition of endothelial tube formation Antiangiogenic Promotion of angiogenesis

Haghighi et al. (2017) Seyfi et al. (2010) Moon et al. (1999)

Angelica sinensis

Promotion of angiogenesis

Artemisia annua

Inhibition of angiogenic factors

Astragalus membranaceus Camellia sinensis

Promotion of angiogenesis

Downregulation of nucleostemin and Oct4 Not elucidated Induction of angiogenesis in the CAM assay Promotion of VEGF and stimulation of JNK 1/2 and p38 phosphorylation Inhibition of major angiogenesis activators such as NO and PGE2 and cytokines VEGF, IL-1β, IL-6, TNF-α Promotion of VEGF, CD34, and eNOS expression Inhibition of VEGF family members

Plants Acorus calamus

Chamaemelum nobile Chresta martii Cinnamomum zeylanicum

Prevention of the new blood vessel formation Antiangiogenic

Lam et al. (2008) Zhu et al. (2013)

Han et al. (2016)

Cao and Cao (1999), Rashidi et al. (2017) Inhibition of VEGFR-2 Guimara˜es et al. phosphorylation (2016) Antiangiogenic Inhibition of NF-κB Queiroz et al. (2018) Inhibition of endothelial cell Inhibition of VEGFR2 kinase activity, Lu et al. (2009) proliferation, cellular migration, and mitogen-activated protein kinase endothelial tube formation (MAPK), and signal transducer and activator of transcription 3 (STAT3) signaling

Chapter 1 • Natural remedies and functional foods

Table 1.4

9

Antiangiogenic functional foods and natural remedies—cont’d

Natural sources

Findings

Combretum hartmannianum Croton crassifolius

Antiangiogenic

Eurycoma longifolia

Galium aparine Galium tunetanum

Gastrodia elata Nicotiana glauca Origanum onites

Panax ginseng

Patrinia villosa

Pinus halepensis

Pithecellobium jiringa Rabdosia rubescens

Inhibition of sprouting of microvessels in rat aortic explants Inhibition of angiogenesis in Suppression of VEGF-A, Ang, and zebrafish embryo model their receptors Inhibition of endothelial cell Inhibition of angiogenesis in CAM proliferation, cellular migration, and assay, rat aortic ring assay, and endothelial tube formation tumor xenograft model Antiangiogenic Inhibition of VEGF secretion Iridoids (Asperuloside, Geniposidic Inhibition of angiogenesis in CAM acid and iridoid V1) of G. tunetanum model inhibit angiogenesis Inhibition of angiogenesis in CAM Inhibition of NO production and assay COX-2 Antiangiogenic Inhibition of sprouting of microvessels in rat aortic explants Antiangiogenic Inhibition of endothelial cell proliferation, cellular migration, and endothelial tube formation Promotion of angiogenesis, Upregulation of eNOS and activation stimulation of endothelial cell of PI3K-Akt pathway proliferation, cellular migration, and endothelial tube formation Antiproliferative, antimigratory, and Induction of focal adhesion kinase antiangiogenic (FAK) and protein kinase B (PKB or Akt) phosphorylation Antiangiogenic Inhibition of endothelial tube formation and angiogenesis in CAM assay Inhibition of cellular migration and Downregulation of VEGF expression tube formation of endothelial cells Antiangiogenic Inhibition of Akt and MAPK kinases

Tamarix nilotica

Inhibition of angiogenesis, endothelial migration, and tube formation Promotion of cell growth and differentiation Antiangiogenic

Tephrosia apollinea

Antiangiogenic

Vitis spp.

Antiangiogenic

Rubus alceifolius

Salvia miltiorrhiza

Mechanisms

Downregulation of VEGF-A expression Upregulation of MMP-2, VEGF, VEGFR2 and Tie-1 Inhibition of sprouting of microvessels in rat aortic explants Inhibition of sprouting of microvessels in rat aortic explants Upregulation of VEGF and Flk-1, and inhibition of MMP-2 secretion

References Hassan et al. (2014) Huang et al. (2015), Wang et al. (2016) Al-Salahi et al. (2013) Atmaca (2017) Camero et al. (2018)

Ahn et al. (2007) Hassan et al. (2014) Bostancıog˘lu et al. (2012) Sengupta et al. (2004), Huang et al. (2005) Jeon et al. (2010)

Kadri et al. (2014)

Muslim et al. (2012) Meade-Tollin et al. (2004) Zhao et al. (2014)

Lay et al. (2003) Hassan et al. (2014) Hassan et al. (2014) Agarwal et al. (2004) Continued

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Functional Foods in Cancer Prevention and Therapy

Table 1.4

Antiangiogenic functional foods and natural remedies—cont’d

Natural sources

Findings

Mushrooms Cordyceps militaris

Inhibition of angiogenesis

Mechanisms

Abrogation of VEGF production, mitigation of Akt1 and GSK-3β activation, and induction of p38α phosphorylation Coriolus versicolor Inhibition of angiogenesis Inhibition of VEGF Ganoderma lucidum Inhibition of endothelial cell Inhibition of VEGF and TGF-β proliferation and angiogenesis 1 secretion Phellinus linteus Inhibition of angiogenesis Inhibition of proliferation, migration, tube formation and VEGF-2 phosphorylation, modulation MMP2, MMP-9, NF-κB, β-catenin, and MAPK expression Pleurotus tuberInhibition of VEGF-induced Downregulation of VEGFR, FGF, regium endothelial proliferation, migration, ANG-Tie, and MMP gene expression and tube formation Traditional name

Ingredients

Natural formulations BuyangAngelica sinensis, Astragalus Huanwu membranaceus, Carthamus tinctorius, Ligusticum chuanxiong, Lumbricus terrestris, Paeonia lactiflora, and Prunus persica Bao-ShenPlacenta Hominis (human placenta), Tiao-Jing-Fang Angelica sinensis, Cuscuta chinensis, Feces trogopterori, and Morindae officinalis Angelica sinensis and Astragalus Dang-Gui-Bu- membranaceus Xue-Tang DangguiShaoyao-San

Aconitum carmichaeli, Alisma orientalis, Astragalus membranaceus, Carthamus tinctorius, Cinnamomum cassia, Lepidium apetalum, Panax ginseng, Periploca sepium, Polygonatum odoratum, Salvia miltiorrhiza, and Seasoned Orange Peel Nue-Jing-Yun- Angelicae sinensis, Cuscuta Yu-Tang chinensis, Ligustrum lucidum, Lycium barbarum, Salviae miltiorrhizae, etc. Qing-Luo-Yin Dioscorea hypoglauca, Phellodendron amurense, Sinomenium acutum, and Sophora flavescens

References Ruma et al. (2014)

Ho et al. (2004) Cao and Lin (2006), Stanley et al. (2005) Lee et al. (2010a), Park (2015)

Lin et al. (2015, 2014)

Findings

Mechanisms

References

Promotion of angiogenesis

VEGFR-2 activation through the PI3K/Akt signaling pathway

Cui et al. (2015), Seto et al. (2016)

Promotion of angiogenesis

Upregulation of VEGF, VEGFR, bFGF, FGF, PDGFR-α, and EGFR

Woo et al. (2007)

Promotion of angiogenesis

Upregulation of VEGFR1/2 expressions and downregulation of sVEGFR1/2 expression Upregulation of eNOS

Lei et al. (2003), Lin et al. (2017), Hu et al. (2018)

Promotion of angiogenesis

Seto et al. (2016), Lan et al. (2012), Ren et al. (2015)

Promotion of angiogenesis



Woo et al. (2007)

Inhibition of angiogenesis

Restoration of the balance of MMP-3 and TIMP-1

Li et al. (2003)

Chapter 1 • Natural remedies and functional foods

Table 1.4 Traditional name Qiliqiangxin

Triphala Churna Tongxinluo

Xiongshao

Xuefu Zhuyu

11

Antiangiogenic functional foods and natural remedies—cont’d Ingredients

Findings

Mechanisms

References

Aconitum carmichaeli, Alisma orientalis, Astragalus membranaceus, Carthamus tinctorius, Cinnamomum cassia, Lepidium apetalum, Panax ginseng, Periploca sepium, Polygonatum odoratum, Salvia miltiorrhiza, and Seasoned Orange Peel Emblica officinalis, Terminalia belerica, and Terminalia chebula

Promotion of angiogenesis

Activation of NRG-1/Akt signaling pathway

Wang et al. (2015a)

Antiangiogenic and antiproliferative Promotion of angiogenesis

Phosphorylation of VEGFR2

Lu et al. (2012)

Dalbergia odorifera, Dryobalanops aromatic, Eupolyphaga seu steleophaga, Hirudo, Mesobuthus martensii, Paeonia lactiflora, Panax ginseng, Periostracum cicadae, Santalum album, Scolopendra subspinipes, and Ziziphus spinosa Ligusticum chuanxiong and Paeonia Promotion of lactiflora angiogenesis

Upregulation of VEGF, PI3K, and Akt signaling pathway

Seto et al. (2016), Chang et al. (2012), Yu et al. (2016)

Upregulation of VEGF and bFGF

Promotion of angiogenesis

Upregulation of VEGF and NO expression

Seto et al. (2016), Lin et al. (2011) Seto et al. (2016), Lin et al. (2018)

Angelica sinensis, Bupleurum chinensis, Carthamus tinctorius, Citrus aurantium, Cyathula officinalis, Glycyrrhiza glabra, Ligusticum chuanxiong, Paeonia lactiflora Pall., Platycodon grandiflorus, Prunus persica, Rehmannia glutinosa Liboschitz

significant side effects such as systemic toxicity, drug resistance, nonselective tissue damage, and potential long-term side effects (Varol, 2015). Thus, recent ethnopharmacological surveys show that many patients and physicians opt and credit natural resources such as plants, mushrooms, lichens, marine organisms, and animals for complementary and alternative medicine. It can be clearly observed that many over-the-counter drugs are derived from natural sources or inspired and synthesized from natural products (Varol, 2018). The discovery of natural angiogenesis modulators is of great importance because angiogenesis is considered a key and common target for many diseases that need urgent discovery of new treatment methods, drugs, and strategies. For example, angiogenesis has emerged as a key process in tumorigenesis, although there are more than 200 types of cancer and cancerous tissue has a morphologically and functionally heterogeneous structure, and is composed of various types of cancer cells with different mutations, epigenetic profiles, and characteristics (Varol, 2017; Hansen et al., 2011). Although there are many

12

Functional Foods in Cancer Prevention and Therapy

Table 1.5

Antiangiogenic natural products.

Natural products

Findings

Mechanisms

References

(2S)-7,20 ,40 -Trihydroxy-5methoxy-8-(dimethylallyl) flavanone

Downregulation of ROS levels and VEGF expression, and G0/G1 phase cell cycle arrest

Zhang et al. (2013a)

4-Amino-2-sulfanylphenol derivatives 4-Hydroxybenzyl alcohol

Inhibition of endothelial cell proliferation, cellular migration, adhesion, and endothelial tube formation Inhibition of protein kinase and angiogenesis Inhibition of angiogenesis

Inhibition of protein kinase B/Akt and ABL tyrosine kinase Downregulation of VEGF, MMP9, and NO production

Xu et al. (2013)

Acacetin

Inhibition of angiogenesis

Aloin

Inhibition of angiogenesis

Arenobufagin

Inhibition of angiogenesis

Aspfalcholide

Inhibition of angiogenesis

Apigenin

Antiangiogenic

Artemisinin

Antiangiogenic

Artesunate

Antiangiogenic

Downregulation of STAT signaling and VEGF expression, inhibition of HIF-1α expression and AKT activation Downregulation of VEGF expression, and STAT3 and VEGFR2 phosphorylation, Downregulation of VEGFR2 signaling pathway Inhibition of VEGF-induced endothelial cell proliferation, cellular migration, and endothelial tube formation Downregulation of HIF-1α and VEGF expression via PI3K/AKT/ p70S6K1 and HDM2/p53 pathways Downregulation of CD31, VEGF, and VEGFR expression, and NF-κB transcriptional activity Downregulation of VEGF, KDR/ flk-1, and PIGF expression

Barbatolic acid

Antiangiogenic

Bavachinin

Inhibition of endothelial tube formation Inhibition of angiogenesis Inhibition of VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures

Bigelovin Brucine

Boswellic acid

Inhibition of angiogenesis

Inhibition of endothelial tube formation and cellular migration Inhibition of HIF-1α and VEGF Inhibition of Ang2 and Tie2 Inhibition of the downstream protein kinases of VEGFR2, including Src, FAK, ERK, AKT, and mTOR and downregulation of VEGF, NO, IL-6, IL-8, TNF-a, and IFN-γ Downregulation of VEGF, CD31, and TGF-β1

Lim et al. (2007), Laschke et al. (2013) Bhat et al. (2013), Liu et al. (2011)

Pan et al. (2013)

Li et al. (2012) Ghalib et al. (2012)

Fang et al. (2007, 2005)

Wei and Liu (2017)

Vandewynckel et al. (2014), Chen et al. (2004) Varol (2018) Nepal et al. (2012) Yue et al. (2013) Saraswati and Agrawal (2013)

Saraswati et al. (2011)

Chapter 1 • Natural remedies and functional foods

Table 1.5

13

Antiangiogenic natural products—cont’d

Natural products

Findings

Mechanisms

References

β-Escin sodium

Antiangiogenic

Wang et al. (2008)

β-Eudesmol

Inhibition of angiogenesis and tumor neovascularization

Inhibition of endothelial proliferation and migration, regulation of TSP-1, ERK, and MAPK levels Inhibition of bFGF and VEGD induced pERK1/2

β-Sitosterol

Promotion of endothelial migration and angiogenesis

Caffeic acid

Inhibition of angiogenesis

Camptothecins

Inhibition of endothelial cell proliferation and tube formation

Celastrol

Antiangiogenic

Chebulagic acid

Antiproliferative, antimigratory, and HUVECs’ permeability inhibition Antiangiogenic

Cucurbitacin E Curcumin

Inhibition of tube formation, migration, and colony formation

Combretastatins

Inhibition of proliferation and vascularization

Deguelin Ellagic acid

Inhibition of tumor vascularization Inhibition of angiogenesis

Emodin

Inhibition of angiogenesis

Induction of VEGF, VEGF receptor Flk-1, and laminin expression Inhibition of VEGF-induced endothelial proliferation, migration, and tube formation, reduction in JNK-1-mediated HIF-1α stabilization Inhibition of HIF-1α, MMP-9, and VEGF through suppression of PI3K/Akt-mediated NF-κB activity and enhancing the Nrf2dependent HO-1 pathway Inhibition of HIF-1α activation, STAT3 phosphorylation, and TLR4-triggered NF-κB activation Inhibition of VEGF-A

Inhibition of VEGFR2-mediated Jak2–STAT3 signaling pathway Regulation of the NF-κB/VEGF signaling, STAT3, proliferatoractivated receptor gamma, IL-4 and IL-13 production, and TAM polarization Inhibition of tubulin assembly, downregulation of VEGF and VEGFR-2 expression Inhibition of the HIF-1α-VEGF signaling pathway Inhibition of VEGF and PDGF receptors, VEGF, MAPK, and PI3K/Akt signaling pathways Inhibition of TRAF6, HIF-1α, VEGF and TRAF6, CD147, MMP9 signaling pathways

Tsuneki et al. (2005), Ma et al. (2008) Moon et al. (1999), Choi et al. (2002) Kim et al. (2009a), Gu et al. (2016)

Jayasooriya et al. (2015), Tsuchida et al. (2003), Kamiyama et al. (2005) Ni et al. (2014)

Lu and Basu (2013)

Dong et al. (2010) Gao et al. (2015), Huang et al. (2017)

Su et al. (2016), Sherbet (2017) Wang et al. (2013a) Labrecque et al. (2005), Wang et al. (2012) Shi and Zhou (2018) Continued

14

Functional Foods in Cancer Prevention and Therapy

Table 1.5

Antiangiogenic natural products—cont’d

Natural products

Findings

Mechanisms

References

Epigallocatechin-3-gallate

Prevention of new blood vessel formation

Inhibition of VEGF signaling

Farnesiferol C

Inhibition of angiogenesis

Fisetin

Inhibition of endothelial cell proliferation, cell-cycle progression, and migration Inhibition of endothelial cell proliferation, migration, and tube formation Inhibition of VEGF-mediated in vitro angiogenesis

Downregulation of VEGF binding to VEGFR1/Flt-1 Downregulation of VEGF and eNOS expression and inhibition of MMPs Inhibition of VEGF and regulation of the PI3K pathway

Cao and Cao (1999), Moyle et al. (2015) Lee et al. (2010b)

Furanodiene

Gallic acid

Genistein

Inhibition of endothelial cell proliferation and angiogenesis

Glyceollins

Inhibition of angiogenesis

Herboxidiene

Antiangiogenic

Heyneanol A

Inhibition of proliferation and tube formation

Honokiol

Antiangiogenic

Hydroxytyrosol

Inhibition of endothelial cell proliferation, cellular migration, and endothelial tube formation Antiangiogenic

Indole-3-carbinol Isoliquiritigenin

Inhibition of neovascularization and tube formation

Inhibition of VEGF secretion, downregulation of AKT phosphorylation and HIF-1α expression, and promotion of PTEN expression Inhibition of VEGF and FGF-2 expression, receptor tyrosine kinase, and suppression of NF-kB, IRF, and Akt signaling pathways Inhibition of VEGFR2, FGFR1, HIF-1α, PI3K, Akt, and mTOR Downregulation of VEGFR2 and HIF-1α Inhibition of bFGF-induced endothelial cell proliferation and capillary tube formation of human umbilical vein endothelial cells Inhibition of HIF pathway Downregulation of MMP-2 expression

Downregulation of PI3K, Akt, mTOR, NF-κB signaling pathways Inhibition of VEGF and VEGFR-2 signaling pathway and downregulation of IRF3/MyD88, ERK/MAPK, JNK/MAPK, Jak1/ STAT1, and PI3K/Akt signaling Pathways

Tsai et al. (2018)

Zhong et al. (2012)

He et al. (2016)

Fotsis et al. (1993), Sasamura et al. (2002), Ruiz and Haller (2006) Lee et al. (2013a, 2015) Jung et al. (2015) Lee et al. (2006)

Vavilala et al. (2014) Fortes et al. (2012)

Ahmad et al. (2013) Wang et al. (2013b), Jhanji et al. (2011), Wu et al. (2015)

Chapter 1 • Natural remedies and functional foods

Table 1.5

15

Antiangiogenic natural products—cont’d

Natural products

Findings

Mechanisms

References

Kushecarpin D

Inhibition of endothelial cell proliferation via G2/M phase cell cycle arrest

Pu et al. (2013)

Lycopene

Inhibition of endothelial cell proliferation, cellular migration, adhesion, and tube formation Antiangiogenic

Chen et al. (2012)

Leucosesterterpenone

Antiangiogenic

Luteolin

Inhibition of VEGF-induced angiogenesis

Inhibition of MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways Downregulation of phosphorylated ERK1/2 Inhibition of VEGF-induced PI3K activity, and VEGFR-2 activitiy

Methylalpinumisoflavones Norisoboldine

Antiangiogenic Inhibition of VEGF-induced endothelial migration Inhibition of angiogenesis

Oleanolic acid Olivetoric acid

Platycodin D

Inhibition of endothelial cell proliferation and tube formation Antiangiogenic

Plumbagin

Inhibition of angiogenesis

Pterogynidine Punarnavine

Inhibition of angiogenesis Inhibition of angiogenesis

Quercetin

Inhibition of angiogenesis

Raddeanin A

Inhibition of angiogenesis

Resveratrol

Inhibition of VEGF-induced angiogenesis

Rhamnazin

Antiangiogenic

Inhibition of HIF pathway Inhibition of cAMP, PKA, NF-κB, and Notch1 signaling pathway Inhibition of VEGFR2, ERK1/2, STAT3, Hedgehog pathways Inhibition of filamentous actin polymerization Inhibition of VEGFR2-mediated signaling pathway Inhibition of VEGFR2-mediated Ras/MEK and Ras/Rac/cofilin signaling pathways Reduction of NF-κB activity Downregulation and inhibition of VEGF, ERK, MMP-2, and MMP-9 Regulation of VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways Inhibition of VEGF-induced phosphorylation of VEGFR2, and PLCγ1, JAK2, FAK, Src, and Akt protein kinases Regulation of Erk1/2, Akt, MAPK phosphorylation, expression of S6 protein, and HIF-1α, IFN-γ secretion, and TAM programming Inhibition of VEGFR2, Akt, MAPK, and STAT3 phosphorylation

Hussain et al. (2008) Bagli et al. (2004), Pratheeshkumar et al. (2012a) Liu et al. (2009) Lu et al. (2013) Niu et al. (2018) Koparal et al. (2010) Luan et al. (2014) Lai et al. (2012)

Lopes et al. (2009) Saraswati et al. (2013a), Manu and Kuttan (2009) Pratheeshkumar et al. (2012b) Guan et al. (2015)

Wu et al. (2018), Jeong et al. (2014)

Yu et al. (2015)

Continued

16

Functional Foods in Cancer Prevention and Therapy

Table 1.5

Antiangiogenic natural products—cont’d

Natural products

Findings

Mechanisms

References

Rhein

Antiangiogenic

Zhou et al. (2015)

Rosmarinic acid

Inhibition of endothelial cell tube formation

Rottlerin

Antiangiogenic

Inhibition of PI3K, Akt, ERK, HIF-1α, VEGF, and EGF Inhibition of endothelial cell proliferation via G2/M phase cell cycle arrest with increase of p21WAF1 expression Downregulation of ECE-1 and inhibition of cyclin D1 and NF-κB

Salvianolic acid B Salvicine

Promotion of cell growth and differentiation Antiangiogenic

Upregulation of MMP-2, VEGF, VEGFR2, and Tie-1 Inhibition of bFGF expression

Santalol

Inhibition of angiogenesis

Secalonic acid D

Antiangiogenic

Silibinin

Antiangiogenic

Sprengerinin C

Antiangiogenic

Streptochlorin

Antiangiogenic

Taxol

Thymoquinone

US Food and Drug Administration (FDA) approved antiangiogenic drug US Food and Drug Administration (FDA) approved antiangiogenic drug Antiangiogenic

Inhibition of VEGFR2-mediated AKT, mTOR, and P70S6K signaling pathway Downregulation of HIF-1α, VEGF, Akt, mTOR, p70S6K signaling cascade Downregulation of HIF-1α, VEGF, COX-2, MMP-9 expression, and PI3K, mTOR pathways, and inhibition of EGFR, ERK, Akt, and STAT3 phosphorylation Inhibition of VEGFR2, PI3K, Akt, mTOR, MAPK, and MMPs Inhibition of TNF-α-induced NF-κB Inhibition of VEGF, HIF-1α production, and disruption of microtubule cytoskeleton Inhibition of VEGF production and disruption of microtubule cytoskeleton Inhibition of VEGF and NF-κB

Trabectedin

Antiangiogenic

Triptolide

Inhibition of proliferation and angiogenesis

Taxotere (Docetaxel)

Upregulation of the inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2 Inhibition of VEGF expression, COX-1, COX-2 and 5-lipoxygenase, and downregulation of NF-κB pathway

Kim et al. (2009b)

Maioli and Valacchi (2010), Valacchi et al. (2011) Lay et al. (2003) Zhang et al. (2013b) Saraswati et al. (2013b) Guru et al. (2014)

Tilley et al. (2016), Kim et al. (2014)

Zeng et al. (2013) Choi et al. (2007) Foa et al. (1994), Escuin et al. (2005) Avramis et al. (2001), Hotchkiss et al. (2002) Paramasivam et al. (2012) Dossi et al. (2015)

Ma et al. (2013), Zhu et al. (2009), He et al. (2010)

Chapter 1 • Natural remedies and functional foods

Table 1.5

17

Antiangiogenic natural products—cont’d

Natural products

Findings

Mechanisms

References

Tylophorine

Inhibition of VEGF-induced cell proliferation, cellular migration, and endothelial tube formation Antiangiogenic

Inhibition of VEGFR2 tyrosine kinase activity and PI3K/Akt/ MTOR signaling pathways

Saraswati et al. (2013c)

Inhibition of VEGF-A, βFGF, STAT3, Akt, p70S6K, and Hedgehog pathways Suppression of VEGFR2mediated AKT and ERK1/2 signaling pathways

Kashyap et al. (2016)

Inhibition of VEGF, VEGFR2, and bFGF Inhibition of VEGF production and disruption of microtubule cytoskeleton Inhibition of VEGF, VEGFR, and HIF-1α

Zhang et al. (2014)

Inhibition of endothelial tube formation Inhibition of MMP-9, VEGF, Akt, and NF-κB

Koparal (2015)

Ursolic acid

Usnic acid

Valproic acid

Inhibition of endothelial cell proliferation, cellular migration, and endothelial tube formation Antiangiogenic

Vincristine

Inhibition of angiogenesis

Voacangine

Vulpinic acid

Inhibition of endothelial cell proliferation, VEGF-induced endothelial tube formation, and chemoinvasion Inhibition of angiogenesis

Withaferin A

Inhibition of angiogenesis

Xanthohumol

Inhibition of angiogenesis

Zerumbone

Inhibition of angiogenesis

Inhibition of AKT and NF-κB pathways Inhibition of NF-κB, VEGF, and IL-8

Song et al. (2012)

Avramis et al. (2001), Mans et al. (2000) Kim et al. (2012)

Lee et al. (2013b), Wang et al. (2015b) Dell’Eva et al. (2007) Shamoto et al. (2014), Tsuboi et al. (2014)

reliable references about the use of a whole organism or its extract as a modulator of angiogenesis, employing this kind of angiogenesis modulator could lead to some side effects. This is because the organism or its extract contains many different compounds that belong to different chemical classes and that might have some detrimental influences along with synergic beneficial activities. Using a whole organism or its extract should be therefore considered as an angiogenesis modulation tool with unpredictable outcomes, and the active substances within these modulators should be isolated in pure forms and investigated to have an angiogenesis modulation tool with predictable outcomes. On the other hand, appropriately taking advantage of the functional foods and nutraceuticals acting as angiogenesis modulators should be considered safe because they already exist in the human diet.

18

Functional Foods in Cancer Prevention and Therapy

Concluding remarks and future perspective It is clear that functional foods and natural remedies are of great importance in complementary, alternative, and/or integrative medicine. Centuries-old traditional knowledge and the modern literature frankly reveal that nature is a substantial and enormous yet entirely unexplored source, although great scientific effort and research funds have been invested in this field by researchers, practitioners, and governments. Great scientific efforts and government financial support, therefore, have continued to be consumed to discover and design novel functional foods and natural remedies. Although both researchers and governments seem to be aware of the importance of natural resources, the natural product studies seem to be in infancy because there is restricted literature about natural product activities on diseases through identifying the related cellular control mechanisms, signal transduction processes, and biological factors. It could be plainly viewed that more in vitro, in vivo, and in silico studies should be performed to identify the multitargets of natural products rather than focusing on a single aspect of the disease. Thus, new combinational treatment strategies can be designed by using natural products as adjuvants or synergistic components. Discovery of functional foods and natural remedies that have a role as angiogenesis modulators has a special significance for employing them as preventive, prophylactic, or therapeutic agents because there are many angiogenesis-borne diseases without convenient medical cures available such as cancer, neurodegenerative diseases, etc. Therefore, more research projects should be developed and more research funds should be provided to light up the activity mechanisms of natural products on the modulation of angiogenesis for employing them to serve for the welfare of patients who have an angiogenesis-dependent disease.

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Ruma, I., et al., 2014. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells. Int. J. Oncol. 45 (1), 209–218. Saik, J.E., et al., 2011. Covalently immobilized platelet-derived growth factor-BB promotes angiogenesis in biomimetic poly (ethylene glycol) hydrogels. Acta Biomater. 7 (1), 133–143. Salajegheh, A., 2016. Angiogenesis in Health, Disease and Malignancy. Springer. Salic, A., Mitchison, T.J., 2008. A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc. Natl. Acad. Sci. 105 (7), 2415–2420. Saraswati, S., Agrawal, S., 2013. Brucine, an indole alkaloid from Strychnos nux-vomica attenuates VEGFinduced angiogenesis via inhibiting VEGFR2 signaling pathway in vitro and in vivo. Cancer Lett. 332 (1), 83–93. Saraswati, S., et al., 2011. Boswellic acid inhibits inflammatory angiogenesis in a murine sponge model. Microvasc. Res. 82 (3), 263–268. Saraswati, S., Alhaider, A.A., Agrawal, S.S., 2013a. Punarnavine, an alkaloid from Boerhaavia diffusa exhibits anti-angiogenic activity via downregulation of VEGF in vitro and in vivo. Chem. Biol. Interact. 206 (2), 204–213. Saraswati, S., Kumar, S., Alhaider, A.A., 2013b. α-Santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/ mTOR/P70S6K signaling pathway. Mol. Cancer 12 (1), 1. Saraswati, S., et al., 2013c. Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2–mediated angiogenesis. Mol. Cancer 12 (1), 82. Sasamura, H., et al., 2002. Inhibitory effect on expression of angiogenic factors by antiangiogenic agents in renal cell carcinoma. Br. J. Cancer 86 (5), 768. Schuch, G., et al., 2002. In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood 100 (13), 4622–4628. Sengupta, S., et al., 2004. Modulating angiogenesis: the yin and the yang in ginseng. Circulation 110 (10), 1219–1225. Seon, B.K., 2015. Dorsal air sac assay. In: Handbook of Vascular Biology Techniques. Springer, pp. 149–151. Seto, S.-W., et al., 2016. Angiogenesis in ischemic stroke and angiogenic effects of Chinese herbal medicine. J. Clin. Med. 5 (6), 56. Seyfi, P., et al., 2010. In vitro and in vivo anti-angiogenesis effect of shallot (Allium ascalonicum): a heatstable and flavonoid-rich fraction of shallot extract potently inhibits angiogenesis. Toxicol. in Vitro 24 (6), 1655–1661. Shamoto, T., et al., 2014. Zerumbone inhibits angiogenesis by blocking NF-κB activity in pancreatic cancer. Pancreas 43 (3), 396–404. Sherbet, G., 2017. Suppression of angiogenesis and tumour progression by combretastatin and derivatives. Cancer Lett. 403, 289–295. Shi, G.H., Zhou, L., 2018. Emodin suppresses angiogenesis and metastasis in anaplastic thyroid cancer by affecting TRAF6-mediated pathways in vivo and in vitro. Mol. Med. Rep. 18, 5191–5197. Shibuya, M., 2006. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 9 (4), 225–230. Smith, S., 2001. Angiogenesis and reproduction. BJOG Int. J. Obstet. Gynaecol. 108 (8), 777–783. Smith, S.M., et al., 2011. A simple protocol for using a LDH-based cytotoxicity assay to assess the effects of death and growth inhibition at the same time. PLoS One. 6(11)e26908. Soares, A., et al., 2010. Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J. Immunol. Methods 362 (1–2), 43–50.

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Targeted cancer therapy with bioactive foods and their products Pankaj Gupta SCHOOL OF MEDI CAL AND ALLIED SCIENCES, K. R. MANGALAM UNIVERSITY, GURGAON, INDIA

Introduction Many prehistoric civilizations such as the Indians, Egyptians, Chinese, and Sumerians suggested that foods are effective in disease prevention as well as treatment. This is evident from the concepts of traditional systems of medicine such as Ayurveda, which describes the health benefits and therapeutic benefits of various bioactive foods. Over time, such foods have been explored for their medicinal value in various countries across the world, and have proven their health benefits. This therefore offers proof of a famous saying by Hippocrates, “Let food be thy medicine.” The age-old analysis of foods was, however, majorly restricted to research pertaining to the flavor, texture, and nutritional components of foods such as proteins, fats, carbohydrates etc. Today’s era, though, is more focused on the chemical components present in food, thereby bridging the link between food and health and providing long-term benefits such as curcumin, which has been reported from turmeric and has been reported to possess anticancer potential. Thus, different foods and their products play a vital role in the normal functioning of the body and are helpful in maintaining the health of the individual and in reducing the risk of various diseases (Asgary et al., 2018). The emergence of this fact led to the evolution of the concept of “bioactive foods,” also known as functional foods or nutraceuticals. These could be envisioned as building blocks of a highly promising concept for the prevention and treatment of diseases. A bioactive food may be defined as any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease. Such products may range from isolated nutrients, dietary supplements, and specific diets to genetically engineered herbal food products and processed foods such as cereals, soups, and beverages (Wan et al., 2018) (Fig. 2.1). Cancer is a leading cause of death worldwide and the IARC (International Agency for Research on Cancer) reported 14.1 million cancer cases worldwide in 2012. That number is expected to rise in the next 20 years to be around 22 million (Stewart and Wild, 2014). Cancer involves abnormal cell growth. These altered cells divide and grow in the presence of signals that inhibit cell growth, hence requiring no specific signal to mutate. The Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00002-8 © 2020 Elsevier Inc. All rights reserved.

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Nutritional components (good health)

+

Medicinal agents (Treatment of diseases)

Bioactive foods (Functional foods / Nutraceuticals) FIG. 2.1 Bioactive foods forming a link between nutritional components and medicinal agents.

resulting mutation causes abnormalities in the cells and daughter cells, resulting in the deaths of some cells and abnormal rapid multiplication in other cells; these abnormal cells get repressed in normal healthy cells. As long as these cells remain in their original location, they are considered benign, but if they become invasive they are considered malignant (Chintale Ashwini et al., 2013). Despite several chemotherapeutic agents that are available commercially, there is a pressing need for newer anticancer agents. This is mainly because of tumor drug resistance, which is a leading cause of chemotherapeutic treatment failure, and also the associated side effects observed with current chemotherapeutic agents (Riganti et al., 2015). Bioactive foods and their products have been implicated for their beneficial role in cancer treatment with fewer adverse effects. Therefore, they are being looked upon as alternative sources of newer anticancer drugs (Zeng et al., 2013). There are several factors involved in the pathophysiology of cancer, mainly tumor metastasis and invasion, proliferation, apoptosis inhibition, free radicals, and angiogenesis (Valastyan and Weinberg, 2011; Rios-Arraba et al., 2013; Zetter, 1998). Several bioactive foods from plants, animals, and microbial sources have been explored and reported for their anticancer potential, although their mechanisms of action may or may not have been elucidated. This chapter focuses and elaborates on such bioactive foods and their products with anticancer potential, and their probable mechanisms of action.

Pathophysiology of cancer Until now, approximately 35,000 genes have been identified from the human genome that have been reported to be associated with cancer due to genetic alterations. The malfunctioning genes can be categorized in three types: 1. Proto-oncogenes: These produce protein products that normally enhance cell division or inhibit cell death. 2. Tumor suppressor genes: These produce proteins that normally prevent cell division or cause cell death. 3. DNA repair genes: These prevent mutations that may lead to cancer.

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The balance between the proto-oncogenes and tumor suppressor genes that are produced during mutations regulates cell growth, wherein the production of the former accelerates cell growth. Tumor progression involves various stages and begins especially from the initial stages, whereby the transformation of normal cells into tumor cells takes place because of uncontrolled cell division, thus forming a malignant mass or tumor. Normal cells require mitogenic growth signals before moving to an active state of proliferation so as to invade host tissues. Several other predominant phenomena that occur during this phase in addition to mutation are the induction of angiogenesis and the resistance to apoptosis (Hanahan and Weinberg, 2000; Angel Nivya et al., 2012). The following six factors are basically common to all types of human tumors: selfsufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis.

Classification of anticancer bioactive foods Chemoprevention can be defined as a phenomenon via which carcinogenesis can be suppressed through natural products or synthetic drugs. Scientific findings have shown that bioactive substances in a dietary food product, even in very low concentrations, may have a far greater impact than previously appreciated on the regulation of cancer mechanisms (Tripathi et al., 2005). Bioactive foods with anticancer potential can be classified using several ways based on their origin (e.g., plant origin, animal origin, etc.), mechanism of anticancer action (e.g., antimetastatic, antiangiogenic, antioxidant, etc.), and the chemical nature of the bioactive anticancer food components (e.g., bioactive foods with phenolic components, flavonoid components, carotenoid components, etc.). 1. The first classification of anticancer bioactive foods is based on their origin, which can be further categorized as: 1.1. Anticancer bioactive foods of plant origin: cereals, vegetables, and beverages. 1.2. Anticancer bioactive foods of animal origin: fish oil, dairy products, and beef. 1.3. Anticancer bioactive foods of microbial origin: mushrooms and probiotics. 2. The second classification of anticancer bioactive foods is based on their mechanism of pharmacological action, which may be further categorized as: 2.1. Anticancer bioactive foods inhibiting metastasis. 2.2. Anticancer bioactive foods inhibiting proliferation. 2.3. Anticancer bioactive foods inducing apoptosis. 2.4. Anticancer bioactive foods inhibiting angiogenesis. 2.5. Anticancer bioactive foods neutralizing free radicals and ROS. 2.6. Anticancer bioactive foods inhibiting matrix metalloproteinases. 2.7. Anticancer bioactive foods inducing DNA methylation.

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3. The third classification is based on the chemical nature of the anticancer bioactive food components, which may be further categorized as: 3.1. Anticancer bioactive foods with phenolic components. 3.2. Anticancer bioactive foods with flavonoid components. 3.3. Anticancer bioactive foods with carotenoid components. 3.4. Anticancer bioactive foods with saponin components. 3.5. Anticancer bioactive foods with fatty acid components. 3.6. Anticancer bioactive foods with sulforaphane components. 3.7. Anticancer bioactive foods with dietary fiber components.

Classification of anticancer bioactive foods based on origin Anticancer bioactive foods of plant origin A number of bioactive foods of plant origin such as cereals, vegetables, and beverages have been reported for their anticancer effects. Cereals come under the category of bioactive foods that are consumed worldwide and have been reported to possess anticancer potential, especially wheat (Triticum aestivum L.), rice (Oryza sativa L.), maize (Zea mays ssp. mays L.), oats (Avena sativa L.), rye (Secale cereale L.), and barley (Hordeum vulgare L.). Whole grain cereals contain diverse phytoconstituents such as phenols, flavonols, etc., that are located mostly in their germ and bran layers (Brown et al., 2015). However, the bran layers of the cereal grains have also been reported as rich sources of glucans and pigments in addition to phenolics and flavonoid components, and have been observed to evince noticeable anticancer activity (Patel, 2012). Rice is one of the most important cereals that have shown anticancer potential. For example, germinated brown rice has been reported to exhibit several physiological effects, including anticancer effects, whereas pigmented rice, which is composed of a variety of components such as flavones, tannin, phenolics, sterols, γ-oryzanols, amino acids, and essential oils, exhibits numerous bioactivities, including antitumor activity (Wu et al., 2013a; Deng et al., 2013). Rice bran has a broad range of bioactive phytochemicals such as ferulic acid, tricin, γ-oryzanol, β-sitosterol, tocopherols, and phytic acid, and has been reported for evincing noticeable anticancer activity against several types of cancers such as leukemia as well as breast, lung, liver, cervical, stomach, and colorectal cancers (Henderson et al., 2012; Chen et al., 2012). Therefore, dietary rice and rice bran have a significant impact on cancer prevention. Barley is another important cereal that has been observed to have a beneficiary role in cancer treatment. Barley grain has a higher content of soluble dietary fibers, which significantly reduces the risk of serious chronic diseases such as colorectal cancer. It also comprises a high content of β-glucans, soluble nonstarch polysaccharides, protein, and lower starch content, which may also play a beneficial role in cancer prevention (Collins et al., 2010; Holtekjolen et al., 2007). Barley grass powder also holds promise to be used as a bioactive food to optimize the health of cancer patients (Venugopal and Iyer, 2010). Therefore, barley may play a very vital role in cancer prevention or treatment.

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Lunasin is a novel cancer-preventive peptide originally isolated from soy but later found in cereals such as barley, rye, and wheat (Nakurte et al., 2013). Wheat straws also hold various bioactive compounds such as policosanols, phytosterols, phenolics, and essential oil, and have been reported for possessing noticeable anticancer activity (Pasha et al., 2013). Vegetables constitute another important class of bioactive foods with anticancer potential. Bitter melon (Momordica charantia L.) is a widely consumed vegetable throughout the world that comprises several bioactive components such as polyphenols, flavonoids, and saponins and has been commonly used as an antidiabetic agent. It exhibited anticancer activity as it was reported to evince a noticeable antiproliferative effect against human prostate cancer cell lines and also proved its effectiveness against breast, colon, and adrenocortical cancers (Pitchakarn et al., 2012; Kwatra et al., 2013). Therefore, bitter melon may act as a preventive bioactive food for the treatment of cancer. Allium vegetables with aromatic properties have been used as a preventive for several types of cancers such as colorectal, breast, ovarian, prostate, and renal cell cancers (Galeone et al., 2006). Allium vegetables including garlic, onions, scallions, chives, and leeks have been reported to reduce the risk of prostate cancer (Hsing et al., 2002). Garlic and its derived compounds (diallyl trisulfide) are promising candidates for breast, skin, colorectal, and prostate cancer prevention (Tsubura et al., 2011). Onions (Allium cepa L.) have proven to be useful for preventing the obesity-related breast, colorectal, laryngeal, and ovarian cancers (Wang et al., 2012). Cruciferous vegetables (e.g., broccoli, cabbage, mustard greens, Brussel sprouts) have generated interest as bioactive foods that may protect against several types of cancers. The high intake of cruciferous vegetables (cabbage and broccoli) was found to be inversely associated with the risk of colorectal, colon, prostate, and bladder cancers in humans (Tang et al., 2010; Liu et al., 2012; Wu et al., 2013b). Beverages such as tea and coffee have also been reported for anticancer potential. Tea is derived from the leaves of Camellia sinensis, a popular beverage throughout the world and now being considered as a functional food due to its usefulness in cancer prevention. The anticancer activity of tea has been attributed to the presence of green tea polyphenols, which are strong antioxidants and have exhibited inhibition of various types of carcinogenesis such as esophageal, stomach, bladder, kidney, urinary tract, colon, rectum, uterus, prostate, liver, lung, breast, pancreas, and skin cancer (Shukla, 2007). The most active polyphenol in green tea is epigallocatechin gallate and it has been observed that its regular consumers showed a noticeable reduction in breast, prostate, and ovarian cancer risk (Ogunleye et al., 2010). Coffee is obtained from the seeds of Coffea arabica L. and is another very popular beverage throughout the world. Its consumption has been associated with a reduced risk of liver cancer and its intake has also been shown to be inversely associated with oral/pharyngeal cancer mortality (Larson and Wolk, 2007; Hildebrand et al., 2013).

Anticancer bioactive foods of animal origin Several bioactive foods of animal origin possessing anticancer potential have been reported such as fish oils, dairy products, beef, etc. As a bioactive food, fish oil has shown

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noticeable beneficial effects in the prevention and treatment of cancer. Due to the higher incidence of cancers and relatively low levels of fish oil intake, it is likely that most people would benefit from fish oil supplementation. Fish oil has been observed to exhibit significant inhibitory effects against various types of human cancers such as breast, colon, skin, pancreatic, prostatic, lung, and larynx cancers (Carroll, 1992; Rose and Connolly, 1992). Fish oil is rich in omega-3 polyunsaturated fatty acid that has been observed to lower the incidence of cancer, the mechanism of action being attributed to the inhibition of metastasis and to tumor cell toxicity, probably by causing lipid peroxidation (Welsch, 1992). Fatty acids such as eicosapentaenoic acid and docosahexaenoic acid that have been obtained from the fish oils of salmon, tuna, mackerel, sardines, and herring have been reported to exhibit potential for the treatment of cancer. Dairy products are the best sources of calcium, an essential dietary mineral commonly found in milk, yogurt, cheese, and dark green vegetables. Several studies have demonstrated that a high calcium intake may decrease the risk of one or more types of cancers with predominant anticancer effects on the colon. Although the exact mechanism of anticancer action of calcium in the colon is unclear, it has been reported that at molecular levels, calcium forms calcium soaps (also known as insoluble complexes) by binding to bile acids and fatty acids in the gastrointestinal tract. This stimulates cell proliferation to repair any cell damage caused by acids or their metabolites. However, calcium may also directly reduce cell proliferation by forcing proliferating cells to undergo differentiation, causing cancer cells to differentiate or die (Milner et al., 2001; Lamprecht and Lipkin, 2001). Some fat components of dairy products, particularly conjugated linoleic acid (CLA) and butyric acid, have been experimentally proven to be effective in the treatment of several types of cancers (Hague and Paraskeva, 1995; Parodi, 1997). Casein, which makes up nearly 80% of the protein in cow milk, has been demonstrated to have anticarcinogenic properties, particularly against colon cancer. The mechanism of action is attributed to the inhibition of enzymes that are produced by intestinal bacteria and are responsible for the deconjugation of procarcinogenic glucuronides to carcinogens (Goeptar et al., 1997; Davoodi et al., 2013). Milk proteins such as casein and especially whey proteins have also been demonstrated to have anticancer effects against breast and prostate cancers, with the probable mechanism of action of bovine whey proteins being attributed to their ability to increase cellular levels of glutathione, which is an antioxidant, or their ability to enhance hormonal and cellmediated immune responses (Parodi, 1998). The beneficial roles of whey proteins, such as lactalbumin, lactoglobulin, lactoferrin, lactoperoxidase, and immunoglobulins, have been well established in the treatment of various types of cancers (McIntosh and Le Leu, 2001). The anticancer component from beef, namely CLA, was first reported in 1987. This is unique in the fact that CLA has been found in fats from ruminant animals such as beef, dairy, and lamb, and increases in foods that are cooked and/or otherwise processed (Ha et al., 1987). This is significant in view of the fact that many mutagens and carcinogens have been identified in cooked meats. CLA has been reported for its effectiveness in suppressing forestomach tumors in mice and mammary carcinogenesis in rats (Ip and Scimeca, 1997).

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Anticancer bioactive foods of microbial origin Bioactive foods of microbial origin such as mushrooms and probiotics have also gained tremendous importance recently because of their anticancer potential. Mushrooms are the fruiting bodies of macroscopic filamentous fungi that grow above the ground and have widely been used as foods and medicines since ancient times throughout the world. A number of anticancer bioactive substances have been identified in many mushroom species such as polysaccharides that have been demonstrated for their activity against breast, colon, gastric, prostate, pancreatic, cervical, and ovarian cancers (Roupas et al., 2012; Wasser, 2002). Phellinus linteus is a well-known fungus with antitumor activity and may play a pivotal role in cancer treatment by acting as an alternative treatment (Sliva, 2010). Many of the boletes are considered to be true delicacies, especially the king bolete (Boletus edulis). The lectin and a biopolymer BE3 from Boletus edulis possess antiproliferative effects, which may provide a new therapeutic option in cancer chemoprevention as Boletus edulis could be incorporated directly into the diet, thereby acting as a bioactive food for the prevention of cancer (Bovi et al., 2012; Lemieszek et al., 2013). Tricholoma matsutake has been regarded as a bioactive food with a great deal of interest as it evinced potential for the treatment of cancer, particularly for oral cancer, the mechanism of action being attributed to its ability to induce apoptosis to inhibit tumor growth (Shin et al., 2012). The World Health Organization (WHO) has defined probiotics as “Live microorganisms (that), when administered in adequate amounts, confer a health benefit on the host.” There are a large number of probiotics available in dairy fermented food, especially in yogurts that are being used widely throughout the world. Some selected strains of Lactobacillus, Bifidobacterium, Streptococcus, Lactococcus, and Saccharomyces have been promoted in food products because of their reputed health benefits. A scientific survey on probiotics supported the therapeutic and preventive use of these bioactive ingredients for various health concerns, including cancer (Sanders, 1999). More evidence supports the role of probiotics in cancer risk reduction, particularly colon cancer, with the probable mechanism of action being attributed to the fact that lactic acid cultures can alter the activity of fecal enzymes (e.g., β-glucuronidase, azoreductase, nitroreductase) that are thought to play a pivotal role in the development of colon cancer (Mital and Garg, 1995). An inverse relationship was also reported on the consumption of fermented milk products and breast cancer risk (Talamini et al., 1984; Van’t Veer et al., 1989).

Classification of anticancer bioactive foods based on the mechanism of action Antimetastatic bioactive foods Cancer is a degenerative disease that involves a higher degree of cell invasion and metastasis. Therefore, one of the prominent mechanisms of anticancer therapy involves

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inhibition of metastasis. Anticancer bioactive foods with antimetastatic properties include fish oil that contains omega-3 polyunsaturated fatty acids, which exhibit anticancer activity via inhibition of metastasis.

Antiproliferative bioactive foods Carcinogenesis is activated by several factors that are involved in cell proliferation and therefore, the antiproliferative mechanism of bioactive foods remains a mainstay for cancer treatment. There are several anticancer functional foods that possess antiproliferative effects such as the bitter melon (Momordica charantia L.); calcium from dairy products such as milk, yogurt, and cheese; lectin; and the biopolymer BE3 from Boletus edulis.

Bioactive foods inducing apoptosis Apoptosis, also known as programmed cell death, is a ubiquitous and highly regulated mechanism involving an energy-dependent cascade of molecular events. Several bioactive foods have shown anticancer activity by inducing apoptosis such as mushrooms, especially Tricholoma matsutake, which has shown a beneficial effect in the treatment of oral cancer.

Antiangiogenic bioactive foods The formation of new blood vessels out of preexisting capillaries or angiogenesis is a sequence of events that is of key importance in a broad array of physiological and pathological processes (Gupta et al., 2014). The switch to the angiogenic phenotype involves a local equilibrium between the negative and positive regulators of angiogenesis. These negative regulators include angiostatin while positive regulators include angiogenin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), etc. Hypoxia has been implicated as a key factor in the progression of microvascular complications that is mediated via VEGF and other positive regulators of angiogenesis (Polverini, 1995) (Fig. 2.2). In several diseases such as cancer (both solid and hematologic tumors), excessive angiogenesis is part of the pathology. These diseases may benefit from the therapeutic inhibition of angiogenesis (Nygren and Larsson, 2003; Gupta, 2014). The basic function of growing tumor cells is to provide nutrients and oxygen to the body tissues, which require an extensive capillary network. Also, the newly formed blood vessels provide a way for cancer cells to enter circulation and proliferate to distant organs. Therefore, cancer treatment requires the therapeutic inhibition of angiogenesis. Several bioactive foods have been reported for their antiangiogenic activity such as turmeric (Curcuma longa L.), which contains curcumin that exhibits an antiangiogenic effect via inhibition of VEGF and bFGF; green tea, which contains polyphenols that inhibit angiogenesis; and red grapes, which contain resveratrol that exhibits antiangiogenic activity via the inhibition of VEGF-induced proliferation of new blood vessels.

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Pathological condition

Release of pro-angiogenic growth factors (bFGF/VEGF) ×

Bioactive foods

Angiogenesis

Cancer FIG. 2.2 Bioactive foods inhibiting angiogenesis pathway.

Anticancer bioactive foods scavenging free radicals Free radicals have been implicated in the pathophysiology of cancer and therefore antioxidant compounds from functional foods may be beneficial in the treatment of cancer. The univalent reduction of molecular oxygen results in reactive oxygen species (ROS). In addition to its fatal effects on the human body such as tissue degeneration, ROS may also join in the generation as well as in the malign transformation of cancer cells (Gupta et al., 2012). If functional food components can enhance the level of antioxidation within the body and clear the ROS in cancer cells, they may inhibit the cell’s growth, thereby playing a vital role in treating cancer. The various bioactive foods with antioxidant potential include garlic, broccoli, green tea, soybean, tomato, carrot, cabbage, onion, cauliflower, red beets, cranberries, cocoa, blackberry, blueberry, red grapes, prunes, and citrus fruits.

Anticancer bioactive foods inhibiting matrix metalloproteinases Matrix metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells, and are responsible for much of the turnover of the matrix components. MMPs, also known as matrixins, consist of 26 members ranging from MMP-1 to MMP-28, and belong to the metzincin superfamily. They are involved in various biological processes such as angiogenesis, apoptosis, etc., and several matrix metalloproteinases have also found expression in various pathological conditions such as cancer (Gupta, 2016). A number of compounds from bioactive foods have shown promising inhibition of matrix metalloproteinases, particularly some flavonoids and phenolic compounds. Phenolic compounds from amla (Emblica officinalis) exhibited inhibition of MMP-1, curcumin from turmeric (Curcuma longa L.) showed inhibition of MMP-2 and MMP-14, and polyphenols from Camellia sinensis exhibited inhibition of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9, thereby exhibiting their potential for cancer prevention.

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Anticancer bioactive foods inducing DNA methylation Carcinogenesis is initiated by a DNA mutation or by an inappropriate expression of genes (oncogenes). These processes lead to decreased methylation of DNA strands, because of which DNA is loosely wound around histone proteins, thus affecting the chromatin structure, gene expression, and genome stability. Such a chromatin thread is exposed to uncontrolled expressions, which in turn cause the synthesis of inappropriate proteins and may lead to cancer development. Disorders of DNA methylation patterns may be important in pathological conditions, including colon cancer. The highest level of methylation occurs in the S phase of the cell cycle (Volpe, 2005). Various elements from bioactive foods are involved in DNA methylation such as folic acid, methionine, and choline. Folic acid is present in green leafy vegetables, cereals, and strawberries. Methionine is found in meat, fish, nuts, mushrooms, and cheese whereas choline is found in eggs, meat, peanuts, and cauliflower.

Classification based on the chemical nature of anticancer bioactive food components Anticancer bioactive foods with phenolic components Phenolics constitute one of the major groups of compounds present in bioactive foods with anticancer potential. Examples of anticancer bioactive foods with phenolic compounds include green tea, rice bran, bitter melon, cocoa beans, ginger, grapes, berries, etc.

Anticancer bioactive foods with flavonoid components Flavonoids are all structurally derived from the parent substance flavone and constitute yet another major group of compounds present in bioactive foods with anticancer potential. Examples of anticancer bioactive foods with flavonoids include bitter melon, pigmented rice, rice bran, etc.

Anticancer bioactive foods with carotenoid components Carotenoids are C40 tetraterpenoids and example of anticancer bioactive foods with carotenoids as the major component include lycopene, which is obtained from tomatoes.

Anticancer bioactive foods with saponin components Saponins are glycosides of medicinal importance and examples of anticancer bioactive foods with saponins as the major components include soybeans, bitter melon, etc.

Anticancer bioactive foods with fatty acid components Examples of anticancer bioactive foods with fatty acids as the major component include cheese and other dairy products as well as beef and other meat products. In all of them, the chief component with anticancer potential has been found to be conjugated linoleic acid.

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Anticancer bioactive foods with sulforaphane components Sulforaphane is the chemical moiety present within the isothiocyanate group of organosulfur compounds. Examples of anticancer bioactive foods containing sulforaphanes as the major component include cruciferous vegetables such as broccoli, kale, and horse radish.

Anticancer bioactive foods with dietary fiber components Dietary fibers are found in the indigestible parts of cereals, fruits, and vegetables. Examples of anticancer bioactive foods containing dietary fibers as the major components are wheat bran, which consists of insoluble fibers that have been reported to reduce the risk of breast and colon cancers.

Conclusion The present chapter entails the various bioactive foods that have been reported for their efficacy in the treatment of cancer. Bioactive foods have gained noticeable attention recently for their inherent pharmacological actions, which may be of immense importance for the treatment of chronic diseases such as cancer. There are several bioactive foods that have been obtained from plant, animal, and microbial sources that have shown noticeable anticancer activity that may be exhibited by varying modes of action. Anticancer bioactive foods may be classified based on their origin, mechanism of pharmacological action, or chemical nature of functional ingredients. Examples of bioactive foods with anticancer potential include cereals, vegetables, beverages, dairy products, fish oil, beef, mushroom, probiotics, etc. Bioactive foods show anticancer effects with varying modes of action such as antimetastatic, induction of apoptosis, antiproliferative, antiangiogenic, scavenging of free radical species, inhibition of matrix metalloproteinases, etc. Anticancer bioactive foods offer tremendous potential for the treatment of various types of carcinogenesis and therefore may act as an alternative for the treatment of cancer. The use of such bioactive foods is, however, limited therapeutically as most of them are being used as dietary sources and the putative active principles responsible for the anticancer effect are yet to be explored. But further studies on such bioactive foods certainly promise the evolution of novel anticancer agents.

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Natural compounds and anticancer effects: The whole is greater than the sum of its parts Simona Martinottia, Elia Ranzatob a

DISI T- DIP A RTI MENTO DI SC IE NZ E E INNOVAZIONE TECNOLOGICA, UNI VE RSI TY OF PIE MONT E ORIENTALE, ALESSANDRIA, ITALY b DISIT-DIPARTIMENTO DI SCIENZE E INNO VAZIONE TE CNOLO G ICA, UNI VE RSI TY OF PI EMO NT E O RI ENTALE , V ER CELL I, IT AL Y

Cancer research The word “cancer” comes from the father of medicine, Hippocrates. He used the Greek word Karkinos to describe tumors, but cancer history begins much earlier. It is difficult to recognize the neoplasm diagnosis in ancient texts just from the literary description. However, progress in understanding and treating tumors has been slow and centered on pathological anatomy development, starting in the 18th century. Cancer is one of the most impactful diseases of the 21st century. Cancer affects people of diverse social, ethnic, and economic factors. In recent years, the genetic, epigenetic, and pathophysiological mechanisms of cancer have been well described, but cancer is still the second-leading cause of death in developed countries, following heart disease (de Oliveira Junior et al., 2018). Cancer cells, to ensure their survival and proliferation, acquire some specific abilities compared to normal cells. During the onset of malignant tumors, they may present constitutively active proto-oncogenes, deactivating the expression of some tumor-suppressor genes. Tumor cells typically show replicative immortality mechanisms (Shay, 2016) and greater resistance to cell death mediated by the regulation of anti- and proapoptotic proteins (Hassan et al., 2014). Chemotherapy is one of the strategies available for tumor treatment. Chemotherapy utilizes compounds capable of preventing proliferative signaling pathways, blocking immortality mechanisms, and preventing angiogenesis, pushing cancer cells toward apoptosis (de Oliveira Junior et al., 2018).

Anticancer products from nature Over the past decades, there has been rising interest in the use of bioactive components from natural sources as potential novel anticancer agents as well as the identification of Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00003-X © 2020 Elsevier Inc. All rights reserved.

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chemical entities, molecular targets, and signaling pathways activated or inhibited by these natural products (Sak and Everaus, 2017). Natural compounds have historically been utilized in cancer treatment, especially in traditional Chinese or Indian Ayurveda medicine. The term “natural compound” specifies chemical substances found in plants, fungi, and marine animals or those produced by microbes, with important pharmacological effects (Rejhova et al., 2018). Many current anticancer drugs, such as the vinca alkaloids vincristine and vinblastine, taxanes (Paclitaxel and Docetaxel), podophyllotoxin derivatives (etoposide and teniposide), and camptothecins such as topotecan (Sak and Everaus, 2017) are classic examples of plant-derived molecules. Actinomycin D and mitomycin C are obtained from Streptomyces and bleomycin is the first marine compound for cancer treatment (Karpinski and Adamczak, 2018). In particular, plant-derived compounds have produced a major contribution to the arsenal of available anticancer drugs; however, less than one-tenth of all terrestrial plants has been evaluated for possible use as cytotoxic agents (Rejhova et al., 2018). Many botanical molecules with assessed positive effects in cancer therapy have a long history. For example, the green tea antioxidant EGCG (epigallocatechin-3-gallate) has been described to significantly slow breast cancer cell growth, but its use was already indicated in ancient Japanese texts. Nature offers an incredible diversity of candidate compounds for fighting tumor growth, whereas the chemical modification of natural molecules can further improve their efficacy and reduce negative effects (Kaur and Verma, 2015). Accordingly, many drugs available for use in clinical practice are direct natural products or obtained by the derivatization of naturally occurring compounds. Up to 70% of the anticancer drugs approved by the US Food and Drug Administration (FDA) come from natural sources (Amin et al., 2009).

Main natural cancer therapeutics The effectiveness of conventional chemotherapeutic drugs has been reduced by several mechanisms, but in particular by drug resistance (Housman et al., 2014). Some studies have recognized that cancer cells exhibit a high degree of tumor mutational burden, making them resistant to the usual cytotoxic drugs. A wide range of natural compounds has been described for use in cancer therapy (Shukla and Mehta, 2015). In fact, products from natural sources are an inexhaustible source of molecules with unique structural models and innovative action mechanisms. Natural compounds are useful in a versatile manner, especially in cancer treatment as chemotherapeutic drugs or for cancer prevention (chemopreventive agents) (Kotecha et al., 2016; Wang et al., 2012).

Tubulin-binding agents The first agents introduced into clinical use were the vinca alkaloids, vinblastine and vincristine, isolated from the Catharanthus roseus, also known as Vinca rosea (Apocynaceae).

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Canadian scientists Robert Noble and Charles Beer were the first to discover Vinca alkaloids in the 1950s. Medicinal applications of this plant led to monitoring these compounds for their hypoglycaemic activity, which is of little importance compared to their cytotoxic effects (Moudi et al., 2013). Vinca alkaloids have been used to treat diabetes and high blood pressure as well as serving as disinfectants. Vinca alkaloids disturb the mitotic spindle assembly by interaction with tubulin. In particular, vinca alkaloids bind specifically to β-tubulin, blocking its ability to polymerize with α-tubulin into microtubules. This leads to the killing of cells in divisions by inhibiting progression through mitosis (Himes, 1991). Vinca alkaloids are normally utilized in combination chemotherapy for medicinal therapies. They do not show cross-resistance with drugs that alkylate DNA and have a different mechanism of action (Lee et al., 2015). The most documented resistance mechanism to vinca alkaloids is due to the multidrug resistance-associated P-glycoprotein (P-gp) as well the multidrug resistance protein (MRP) (Zhang et al., 2017). Moreover, the overexpression of Bcl-XL and Bcl-2 proteins can protect cells to vincristine and vinblastine exposure in the absence of P-gp or other drug-resistant associated genes (Simonian et al., 1997). There are other microtubule destabilizing agents such as cryptophycins, dolastins, and halicondrins. Cryptophycins are a class of dioxadiazacyclohexadecenetetrone cytotoxins with a strong ability to make tubulin depolymerization. The cryptophycins were first isolated from the cultures of the Nostoc cyanobacteria in the early 1990s. Cryptophycins bind microtubules at the vinca-binding site determining a mitotic arrest (Shih and Teicher, 2001). Dolastatins are peptides originally isolated from the marine Indian Ocean sea mollusk Dolabella. Dolastatins, as small linera peptide molecules, are considered promising antitumor molecules showing effectiveness against breast and liver cancers, solid tumors, and some leukemias (Negi et al., 2017). These molecules noncompetitively inhibit binding of vincristine to tubulin (at a location known as the vinca/peptide region) (Amador et al., 2003). Halicondrins, in particular halichondrin B, were first isolated from the Japanese sponge Halichondria okadai. They are noncompetitive inhibitors of vinblastine binding to tubulin, inhibiting microtubule formation through binding at a unique site within the vinca domain (Lichota and Gwozdzinski, 2018). Taxanes are chemotherapeutic agents, including paclitaxel and docetaxel, determining anticancer effects by causing the stabilization of cellular microtubules, thereby inhibiting cell division (Fauzee, 2011). Taxanes are also plant-derived spindle poisons, although they work through a different mechanism than the vinca alkaloids, causing a spasm of the spindle rather than paralysis (Ojima et al., 2016). Paclitaxel and docetaxel have very high activity against some solid tumors (ovarian, breast, lung, head and neck, etc.) and in some hematological and pediatric cancers (de Weger et al., 2014). Both drugs are active as single agents and in combination chemotherapy. The major dose-limiting toxicity of taxanes is profound myelosuppression as well as hypersensitivity reactions and neuropathy.

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Topoisomerase inhibitors The nuclear enzymes topoisomerase I and II are considered critical for some specific functions such as DNA function and cell survival. Moreover, recent studies have recognized these proteins as pivotal targets for several clinically active anticancer drugs. In fact, topoisomerases act to reduce torsional stress in supercoiled DNA molecules. They allow selected regions of DNA to become sufficiently untangled and relaxed in order to allow activity such as replication, recombination, repair, and transcription. The complete or only partial inhibition of the topoisomerase mechanism results in the accumulation and stability of cleavable complexes and subsequent death of the cell (Chen and Liu, 1994). Inhibitors of topoisomerase I and II are antitumor molecules active in a variety of hematological and solid neoplasms. The plant-derived camptothecins (irinotecan, topotecan) act as inhibitors of topoisomerase I; the plant-derived epopodophyllotoxins (etoposide and teniposide) and the microbial-derived anthracyclines (e.g., doxorubicin, epirubicin) act as inhibitors of topoisomerase II (Houghton et al., 1995; Marinello et al., 2018). In 1966, campthotecin was recognized as the active constituent of the extract of the Chinese tree Camptotheca acuminate, and it showed activity against a variety of leukemias and solid tumors (Hevener et al., 2018). In 1996, two semisynthetic camptothecin analogues, irinotecan and topotecan, started to be utilized for the treatment of colorectal and ovarian tumors (Malonne and Atassi, 1997). Now, several synthetic camptothecin analogues are available for clinical evaluation (e.g., lurtotecan, exatecan mesylate, karenitecin, gimatecan) (Martino et al., 2017). Different cellular mechanisms of resistance to camptothecins, mainly dependent on ATP transporters such as P-gp and MRP, have been described (Pommier, 2006). Podophyllotoxin is a natural molecule isolated from Podophyllum peltatum and Podophyllum emodi. Etoposide (VP-16), a podophyllotoxin derivative, is utilized in the treatment of many tumors, particularly small cell lung carcinoma and testicular cancer (Hevener et al., 2018). This compound is able to induce cell growth arrest by inhibiting DNA topo-isomerase II, which causes double strand breaks in DNA. VP-16 does not induce tubulin polymerization inhibition. However, its parent compound, podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a potent inhibitor of microtubule assembly (Damayanthi and Lown, 1998). Anthracyclines have been an integral part of the chemotherapeutic regimen since their discovery in the 1960s. Anthracyclines are extracted from Streptomyces bacterium such as Streptomyces peucetius var. caesius. The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is obtained from Streptomyces peucetius. Doxorubicin (trade name Adriamycin) was developed shortly after and approved for medical use in the United States in 1974 (Tacar et al., 2013). Anthracyclines determine the inhibition of the topoisomerase II relegation reaction, producing an accumulation of protein-linked double- and single-strand DNA breaks, which ultimately lead to cytotoxic DNA damage

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and cell death (Tacar et al., 2013). Recently, anthracyclines have come under scrutiny due saubry, 2018). to their cardiotoxic effects (Nebigil and De Anthracyclines are also able to induce free oxygen radical production by at least two distinct pathways (Sinha, 1989), but it is not clear if this contributes to cell death and antiproliferative effects (Mordente et al., 2017). Anthracyclines are used to treat leukemias as well as a wide range of solid tumors such as lung cancer, breast cancer, gynecological cancers, and sarcomas (Minotti et al., 2004). All anthracyclines are substrates for the P-gp-mediated drug efflux pump, representing the main mechanism of cellular resistance to these drugs (Nobili et al., 2006).

Other drugs from natural sources The cancer-preventive effects of tea polyphenols, in particular epigallocatechin-3-gallate (EGCG), have been validated by epidemiological, preclinical, and clinical studies (Martinotti et al., 2014b). The history of tea consumption dates back around 5000 years ago to ancient China. Now, tea is the most popular beverage consumed. Green tea, black tea, and oolong tea are all derived from the Camellia sinensis plant and contain a variety of compounds, the most significant of which are polyphenols (Khan and Mukhtar, 2018). Tea polyphenols contribute to preventive effects on various pathological conditions, including cancers (Chen et al., 2008). The anticancer effects of tea polyphenol and of EGCG in particular were described in various cancer cell lines, animal models, and clinical studies (Thota et al., 2018). Apparently, EGCG functions as a powerful antioxidant preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent as well as a modulator of cancer cell response to chemotherapy (Martinotti et al., 2015). In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways, including JAK/STAT, MAPK, PI3K/AKT, Wnt, Notch, and unfolded protein response (UPR) interacting with glucose-related protein-78 (GRP78) (Martinotti et al., 2014a, 2018; Ranzato et al., 2012). Vitamin C (ascorbic acid, ascorbate) has an intriguing history, as the interest in its use as a cancer treatment began as long ago as the 1970s, when it was revealed that some properties of this vitamin might make it toxic to tumor cells. Initial studies in humans had promising results, but these studies were later found to be flawed. In vitro studies showed that pharmacological doses of vitamin C (0.1–100 mM) are able to reduce viability in cell lines in various types of tumors (Ranzato et al., 2011). The mechanism of vitamin C toxicity is linked to its prooxidative behavior by means of chemical reactions that produce hydrogen peroxide, exerting cytotoxic effects on cancer cells (Martinotti et al., 2017). Rapamycin was initially recognized as an antifungal metabolite produced by Streptomyces hygroscopicus from a soil sample of Easter Island (also known as Rapa Nui). Then, rapamycin showed immunosuppressive and antiproliferative properties in mammalian

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cells (Yoo et al., 2017). Rapamycin acts as a specific inhibitor of m-TOR (mammalian target of rapamycin) that is a downstream mediator of PI3K/Akt. Thus, it selectively blocks transcriptional activation, leading to tumor cell growth and division (Li et al., 2014). The poor solubility and pharmacokinetics of rapamycin have triggered the development of several rapamycin analogs (rapalogs). Two water-soluble derivatives of rapamycin, temsirolimus and everolimus, were approved by the FDA in 2007 and 2009 (Wander et al., 2011). L-Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia and are also utilized for remission induction and intensification treatment in all pediatric regimens and in the majority of adult protocols. The cancer-inhibitory properties of the bacterial enzyme L-asparaginase were discovered more than 50 years ago (Izadpanah Qeshmi et al., 2018). L-Asparaginase is a hydrolase that catalyzes L-asparagine conversion in an endogenous amino acid necessary for the function of cancer cells. A recent study indicated that L-asparaginase inhibited mTORC1, activating apoptosis as well as the autophagy process in acute myeloid leukemia cells (Song et al., 2015). Although L-asparaginase is present in various plant and animal species, microorganisms are the most efficient and inexpensive sources of this enzyme. L-Asparaginase is utilized in multidrug chemotherapy in children and adults with acute lymphoblastic leukemia, contributing to a significant improvement of therapy outcomes with a complete remission in about 90% of patients. Notwithstanding its high therapeutic efficacy, L-asparaginase can increase thrombosis risk ( Jovic et al., 2013). Trabectedin (also called ET-743, ecteinascidin 743, and Yondelis) is a product obtained from the extensive plant and marine natural product isolation and screening program pursued in the 1960s. The tetrahydroisoquinoline alkaloid was originally extracted from the sea squirt Ecteinascidia turbinata, and its anticancer activity was discovered 15 years before its successful structure elucidation. Since 2007, trabectedin has been approved for patient treatment with soft tissue sarcoma in Europe, and it is in clinical evaluation for other tumor types (Le Cesne et al., 2005). Trabectedin binds to guanines in the minor groove of DNA through an iminium species that is generated by a dehydration of the hemiaminal function (Carter and Keam, 2007). Hydrogen bond formation and van der Waals stabilization with nucleotides on the opposite strand of the DNA double helix create an equivalent to a DNA cross-link, bending the DNA backbone and interfering with the gene transcription process (D’Incalci et al., 2014).

Cancer prevention or natural chemopreventive agents An alternative approach is chemoprevention, which consists of using synthetic, semisynthetic, or natural agents to inhibit or reverse the carcinogenesis process, particularly in individuals with a high risk of developing cancer (Lewandowska et al., 2014). Some epidemiological studies showed that the incidence of some cancers in Asia (such as breast, colon, prostate, and lung cancers) is lower than, for instance, in Europe and the

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United States ( Jemal et al., 2011; Liu, 2003). This low incidence may result from the beneficial effects of the plant-derived polyphenols in Asian diets rather than European or American diets. It may be a consequence of drinking high amounts of green tea (for the presence of catechins) (Schramm, 2013) as well as consuming large amounts of soy products that contain genistein (Mohammad et al., 2006). The results of recent studies indicate that natural compounds derived from edible and therapeutic plants could be used in both the prevention and therapy of cancer, as they act pleiotropically on tumor cells. These natural molecules can affect a huge number of signaling pathways, exhibiting a variety of biological activities including antiproliferative, proapoptotic, and antiangiogenic activities (Gorlach et al., 2011). Moreover, there is an increasing body of evidence on the stronger chemopreventive activities of combinations of phytochemicals than in the case of individual compounds, which is referred to as a synergistic effect (de Kok et al., 2008). Some compound combinations exhibit biological activity that is not detected when its individual constituents are tested separately (Lewandowska et al., 2014).

An example of synergistic interaction The use of combination chemotherapy is the accepted standard for most human cancers, but little attention has been paid to drug interactions. A combination of drugs may be synergistic, additive, or antagonistic in cytotoxic activity (Budman and Calabro, 2002). Natural compounds such as vitamin C and EGCG have been largely evaluated in combined treatment with clinically used chemotherapeutics. These compounds are widely found in various medicinal plants and foods, such as red wine, fruits, vegetables, and spices. The use of these kinds of molecules has been progressively encouraged in cancer treatment protocols, mainly because of their low toxicity and immediate availability (de Oliveira Junior et al., 2018). Ranzato et al. (2011) revealed that ascorbate is selectively cytotoxic toward mesothelioma cells, showing that ascorbate-induced extracellular H2O2 production induces a strong oxidative stress in mesothelioma cells due to their high superoxide production rate. Hence, by considering that at concentrations that are toxic for mesothelioma cells, ascorbate is well tolerated by the human body. Martinotti and colleagues (Martinotti et al., 2011) tested classic chemotherapeutic drugs for mesothelioma therapy such as cisplatin, etoposide, gemcitabine, imatinib, paclitaxel, and raltitrexed. Due to the strong need of novelties in mesothelioma therapy, other new drugs have been included in this screening such as epigallocatechin-3-gallate (EGCG). Isobologram analyses, based on in vitro cytotoxicity tests, demonstrated synergistic interactions of ascorbate with EGCG and gemcitabine (Martinotti et al., 2011). Moreover, Martinotti and coworkers showed that the AND mixture (i.e., active nutrients/drug, a combination of ascorbate, EGCG, and gemcitabine) induces in mesothelioma

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Classic chemotherapic drug EGCG H2O2

Ascorbate H2O2

FIG. 3.1 EGCG and ascorbate act synergistically with classic chemotherapeutic drugs to induce cell death.

cells cell cycle deregulation and apoptosis. The mechanism is synergistic and involves an impairment of free cytosolic Ca2+, the DAPK2 upregulation of as well as the repression of NF-κB, and a block of cell cycles that prevents cells from entering into the G2/M phase (Martinotti et al., 2014c). In vivo experiments on a xenograft mouse model for mesothelioma, obtained in immunocompromised mice, showed that AND strongly reduced the primary tumor size as well as the number and size of metastases, preventing abdominal hemorrhage. Moreover, Kaplan Meier curves and the log-rank test indicated a marked increase in the survival of AND-treated animals. The complex data showed that the AND treatment is synergistic in vitro on mesothelioma cells, and blocks in vivo tumor progression and metastasization in xenografts (Volta et al., 2013) (Fig. 3.1).

Conclusion In vitro and in vivo studies have confirmed that natural products can act synergistically with drugs traditionally used in tumor therapy, enhancing their antitumor efficacy through various mechanisms, including apoptosis induction and inhibition of cell proliferation, invasion, metastasis, and angiogenesis (de Oliveira Junior et al., 2018). Although the in vivo tests are limited and in some cases with moderate methodological quality (de Oliveira Junior et al., 2018), it is easy to understand the potential of natural products as anticancer drug candidates in future clinical research for combinatorial treatments.

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The use of natural molecules for cancer cell chemosensitization is a recent strategy and this approach should be expanding rapidly in the coming years, providing efficient alternatives to cancer growth and tumor chemoresistance management (de Oliveira Junior et al., 2018).

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Simonian, P.L., Grillot, D.A.M., Nunez, G., 1997. Bcl-2 and Bcl-XL can differentially block chemotherapyinduced cell death. Blood 90, 1208–1216. Sinha, B.K., 1989. Free radicals in anticancer drug pharmacology. Chem. Biol. Interact. 69, 293–317. Song, P., Ye, L., Fan, J.J., Li, Y.B., Zeng, X., Wang, Z.Y., Wang, S.F., Zhang, G.P., Yang, P., Cao, Z.L., Ju, D.W., 2015. Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells. Oncotarget 6, 3861–3873. Tacar, O., Sriamornsak, P., Dass, C.R., 2013. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J. Pharm. Pharmacol. 65, 157–170. Thota, S., Rodrigues, D.A., Barreiro, E.J., 2018. Recent advances in development of polyphenols as anticancer agents. Mini Rev. Med. Chem. 18 (15), 1265–1269. https://doi.org/10.2174/13895575 18666180220122113. Volta, V., Ranzato, E., Martinotti, S., Gallo, S., Russo, M.V., Mutti, L., Biffo, S., Burlando, B., 2013. Preclinical demonstration of synergistic active nutrients/drug (AND) combination as a potential treatment for malignant pleural mesothelioma. PLoS One 8, e58051. Wander, S.A., Hennessy, B.T., Slingerland, J.M., 2011. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Investig. 121, 1231–1241. Wang, H., Khor, T.O., Shu, L.M., Su, Z.Y., Fuentes, F., Lee, J.H., Kong, A.N.T., 2012. Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anti Cancer Agents Med. Chem. 12, 1281–1305. Yoo, Y.J., Kim, H., Park, S.R., Yoon, Y.J., 2017. An overview of rapamycin: from discovery to future perspectives. J. Ind. Microbiol. Biotechnol. 44 (4–5), 537–553. https://doi.org/10.1007/s10295-016-1834-7. Zhang, Y., Yang, S.H., Guo, X.L., 2017. New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer. Biomed. Pharmacother. 96, 659–666.

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Relationship between functional food and tumor metabolism

Mohammad Mostafizur Rahmana, Md. Abdul Khalequeb a

LABORATORIES OF C ELL AND MO LECULAR BIOLO GY , NATIONAL INSTITUTE O F DIABETES AND DIGESTIVE AND KIDNEY DISEASES, BETHESDA, MD, UNITED STATES b DEPARTMENT OF BIOCHEMISTRY AND MICROB IOLOGY, NORTH SOUTH UNIVERSITY, DHAKA, BANGLADESH

Introduction: Functional foods Cancer is the second-leading cause of death every year, following cardiovascular disease. The majority of deaths associated with cancer are considered being preventable worldwide. An effective intervention can reduce mortality and human disability arising from cancer (Aghajanpour et al., 2017; Wilson et al., 2017). Many known nutrients, nonnutritive food ingredients, and botanicals are reported to mitigate cancer severity in addition to their well-established effect on chronic diseases such as diabetes, hypertension, osteoporosis, and asthma. A functional food is a food considered to promote good health and prevent diseases and, in some instances, help mitigate the severity of chronic disease symptoms (Goetzke et al., 2014). Antioxidants in common fruits or vegetables are termed “functional” components in a functional food. Phytochemicals are present in whole grains, soy, herbs, and spices such as parsley, chives, garlic, and ginger. Phytochemicals are also present in many fruits and vegetables. Both antioxidants and phytochemicals are considered to be health-promoting factors and disease-preventing components in functional foods (Krishnaswamy, 1996). The term is also applied to traits purposefully bred into an existing normal or regular food, for example, potatoes enriched in anthocyanin or carotenoid (Brown et al., 2003). In most cases, functional foods are similar to conventional foods, and are often consumed as a regular diet (Ozen et al., 2012). Functional foods are designed to deliver physiological benefits, that is, preventing chronic diseases beyond providing only basic nutrition. The role of functional foods is supported by epidemiological studies, and clinical trial data indicate that a formulated diet may reduce the risk of chronic diseases (Rajasekaran and Kalaivani, 2013; Hefferon, 2015; www. eatright.org). Functional foods range from cereals and bars to tomatoes or green tea while the active ingredients present in these foods are also available in pill form, popularly known as dietary supplements (Bigliardi and Galati, 2013; Katan and Roos, 2004; Khan et al., 2006). Natural food or food products, in other words unmodified foods such as fruits and vegetables, are examples of the simplest form of functional foods. Unmodified functional Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00004-1 © 2020 Elsevier Inc. All rights reserved.

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foods such as carrots and tomatoes are high in beta carotene and lycopene, physiologically active compounds known to have a significant role in the cellular metabolism (Sloan, 2002). Whole grains and fibers are present in all breads and cereals. Among all foods, milk is so far the best source of calcium. Fortified or altered functional foods are naturally or artificially enhanced with additional ingredients or nutrients of choice (Kaur and Singh, 2017). Margarine is fortified with plant sterol and prebiotics/probiotics (enriched products), and eggs fortified with omega-3 are produced through altering chicken feed (enhanced products). Additionally, both vitamin D-fortified milk and vitamin C-fortified fruit juices are popular in US supermarkets (Williamson, 2018; Siro et al., 2008). Here is a list of functional foods found in US markets compiled by the Academy of Nutrition and Dietetics (Williamson, 2018; Siro et al., 2008; Kumar and Pandey, 2013), which is the world’s largest organization of nutrition professionals (https://www. eatright.org/food/nutrition/healthy-eating/functional-foods). (1) Cold-water fish (sardines and salmon). Functional components are omega-3 fatty acids, that is, DHA and EPA. (2) Fortified margarines. Functional components are plant sterol and stanol esters. (3) Soy. Functional components are isoflavones, genistein, and soy protein. (4) Tomatoes and tomato products. Functional component is lycopene. (5) Nuts. Functional components are monounsaturated fatty acids and vitamin E. (6) Grape juice or red wine. Functional component is resveratrol. (7) Berries. Functional component is anthocyanin. (8) Leafy greens. Functional components are carotenoids, sulforaphanes, apigenin, and lutein/zeaxanthin. (9) Omega-3 enriched eggs. Functional components are omega-3 fatty acids, that is, DHA and EPA. (10) Oats. Functional components are ß-glucan and saponins. (11) Whole grains (barley). Functional components are fiber and phytochemicals. (12) Probiotics. Functional component is typically lactobacillus. Over the last decade or so, a large number of nonnutrient molecules have been identified as beneficial. These include flavones (secondary metabolites), which are reported to protect against heart diseases, and soy-based estrogens, which are reported to protect against tumorigenesis (Kumar and Pandey, 2013; Prieur et al., 1994). The American Dietetic Association (ADA) classifies functional foods as designer foods. The ADA cautioned that it should not be implied that functional foods are better food than unmodified natural food. According to the ADA, all foods are functional at some physiologic level and can be incorporated into a healthy meal plan; the key is in moderation and usage of a variety of foods (Hasler et al., 2004; Hasler and Brown, 2009). The Food and Drug Administration (FDA) suggests that functional foods be placed in categories such as conventional/natural food additives, dietary food supplements, and foods for special dietary use/requirements under the Dietary Supplement and Health and Education Act (DSHEA) of 1994. It allows the usage of dietary supplement claims on functional foods without the FDA’s prior

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authorization. Such statements by functional food marketing companies describe how an ingredient in food affects cellular function, for example, calcium that builds strong bones. The scientific merit of functional foods as claimed is often limited and potentially disputable. The ADA recommends that functional foods be regulated to ensure that the products are safe. The ADA recommends that functional food preparation and manufacture must use standard good manufacturing practices (GMP), and all functional food labels should publish nutrient content, an ingredient list, and information about the chemical structure/function. The ADA also recommends that the claims made are truthful and are always based on sound scientific research (Hasler and Brown, 2009; Milner, 2000).

Functional foods exert their beneficial effects mostly through cellular metabolism The human gut is a vast selective nutrient absorption system that is actively involved in nutrient recognition and signal transduction in our body. Functional foods mostly exert their beneficial effects through cellular metabolism (Wang, 2012; Wan et al., 2018). Dietary fibers and oligosaccharides utilize signaling pathways in the human gut. Flavonoids belong to a group of natural chemical substances containing variable phenolic compounds found in fruits and vegetables. Flavonoids are also found in moderate amounts in grains, barks, roots, stems, and flowers. Flavonoids are also present in a considerable amount in tea and wine. Flavonoids are an indispensable ingredient in a variety of nutraceutical, pharmaceutical, medicinal, and cosmetic products. The antioxidative, antiinflammatory, antimutagenic, and anticarcinogenic properties of flavonoids coupled with their capacity to modulate key cellular enzyme function (Kumar and Pandey, 2013; Lotito and Frei, 2006; Chen et al., 2014a, b) make them key modulators of immunomodulation, cell-to-cell communication, and various kinds of prostaglandin production (Park et al., 1998).

Metabolic dysregulation in tumor cells Tumor cells are characterized by their unique ability to rapidly proliferate. An increased rate of proliferation creates a high demand for energy and building block materials. In tumor cells, an increased rate in cell division requires a rapid duplication of its genome, organelles, cellular protein, and lipids. In a highly proliferative tumor tissue, an enhanced rate of glycolysis fulfills the high ATP demand (Fig. 4.1). The requirement of protein, fatty acid, and nucleotide biosynthesis in cancer cells is primarily fulfilled by glucose as the carbon source (Vander Heiden et al., 2009; Hanahan and Weinberg, 2000, 2011). The current literature suggests that the ability to modulate or reprogram the metabolism is central to support various kinds of tumor cell proliferation (Vander Heiden et al., 2009). A dysregulated metabolism is commonly observed in tumor cell lines derived from all types of cancer patients, but the fate of glucose and other nutrients in tumor cells growing

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FIG. 4.1 Metabolic differences between normal and tumor tissues.

in an in vivo microenvironment is largely not well understood. Most of our understanding of an altered tumor metabolism is primarily based on recent in vitro tissue culture studies (DeBerardinis et al., 2008).

Tumor metabolism: Glycolysis and acidosis In a normal tissue, glucose is not usually metabolized to lactate when oxygen is available. Only in a limited situation do normal cells utilize the anaerobic breakdown of glucose into lactic acid. High glucose consumption is a common feature in tumor tissues that helps increase the rate of glycolysis under aerobic conditions to generate ATP (Kato et al., 2018). Most of the lactate thus produced is released into extracellular space (Kato et al., 2013), and its concentration in various tumor tissues varies widely, that is, from 10 mM to 30 mM (Walenta et al., 2016). The extracellular pH of tumor tissues is around 6.5, or lower than that in many instances. Interestingly, blood lactate concentration is often not affected in most cancer patients, despite lactate production by tumor cells (Engin et al., 1995). Lactate in blood not only fuels tumor cell proliferation, but is also reported to enhance metastasis upon uptake through monocarboxylate transporters (MCT) or binding to G-protein coupled receptors such as GPR81 (Le Floch et al., 2011). MCTs are key in lactate transport in most tumor tissues. The key glucose transporter GLUT-1 is overexpressed in various types of tumor cells and is implicated in the poor prognosis from many types of tumors (Szablewski, 2013; Semenza, 2008). The glycolytic pathway is not only a source of energy in highly proliferative tumor cells, but it also facilitates the rapid production of nucleotides, fatty acids, and amino acids (Fig. 4.2). During glycolysis, glucose-6-phosphate (G-6P) is diverted through the enzyme G-6P dehydrogenase (key enzyme in the pentose phosphate pathway) into ribose-5phosphate for nucleotide synthesis. The same reaction also helps the regeneration of cellular electron carriers such as NADPH. Glyceraldehyde-3-phosphate or dihydroxyacetone phosphate is required for the biosynthesis of cell membrane components such as phospholipids and triacylglycerols. In tumor cells, amino acids (for example, serine, cysteine, and glycine) are generated from the 3-phosphoglycerate dehydrogenase (PHGDH)catalyzed conversion of 3-phosphoglycerate into serine. Most cancer tissues can switch

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FIG. 4.2 Enhanced glycolysis supplies necessary precursors for biosynthetic pathways critical to highly proliferative tumor cells.

to aerobic glycolysis, although it is unclear why tumor cells reprogram to glycolysis that is nearly 18-fold lower in ATP production relative to OXPHOS (Fig. 4.2). Possibly this switch in cancer cells is essential as enhanced glycolysis facilitates the biosynthesis of all the nucleotides and amino acids essential for cellular growth in rapidly proliferating tumor tissues (Semenza, 2008; Gatenby and Gillies, 2004).

Tumor metabolism: Mitochondria and altered TCA cycle fate Accelerated glycolysis and a decrease in oxidative phosphorylation constitute the basis for the Warburg effect in cancer tissues. In several kidney, breast, and colon carcinomas, cells exhibit alterations in frataxin and a decrease in expression of the mitochondrial beta-F1-ATPase in parallel with a significant increase in glyceraldehyde-3-phosphate dehydrogenase enzyme activity (Isidoro et al., 2005; Moreno-Sanchez et al., 2009). Genetic alterations in the p53 gene, one of the frequently mutated genes in most tumor cells, is assumed to be associated with increased lactate production through pyruvate dehydrogenase (PDH). Furthermore, mutations in numerous mitochondrial enzymes, that is, fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase

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FIG. 4.3 Glucose is the central carbon source in the tumor metabolism.

(IDH), have been reported previously in a number of tumor cells (Tomlinson et al., 2001; Romero-Garcia et al., 2011). Glutamine is the second most important nutrient for proliferating cells besides glucose. Recently, myc an oncogene has been shown to stimulate mitochondrial glutaminolysis, which can lead to the glutamine addiction of tumor cells. An imbalance that negatively affects the glutathion redox control system thereby influences the viability of tumor cells. For example, the mouse model of primary human glioblastoma (GBM) displayed metabolic complexity compared to the surrounding tissue. In vivo, tumor cells metabolize glucose via pyruvate dehydrogenase and the tricarboxylic acid (TCA) cycle (Fig. 4.3), but accumulate a large pool of glutamine (Romero-Garcia et al., 2011; Marin-Valencia et al., 2010; Payen et al., 2016). Tumor tissues do possess functional mitochondria and perform mitochondrial oxidative respiration. A respiratory deficiency is not the reason why tumor cells usually exhibit high glycolytic activity. The rate of ATP generation through enhanced glycolysis is higher than what can be achieved through mitochondrial respiration in proliferative cells (Fig. 4.3). Because tumor cells utilize multiple pathways through which a high level of glucose is metabolized, the glycolytic pathway seems to be sufficient to the increased energetic need of tumor cells, that is, ATP, nucleotide, and protein biosynthesis (Vander Heiden et al., 2009; Payen et al., 2016; Vander Heiden, 2013).

Functional foods: Metabolic reprogramming in tumor cells and emerging concepts in therapeutic strategies It is debatable whether an individual food can be healthy or unhealthy, as it is the composition of the entire diet that mainly determines nutritional status in an individual. For example, increased consumption of whole grains might prevent heart disease in adults

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but may cause malnutrition in rapidly growing infants (Siro et al., 2008). This has created a market for food that combines short- or long-term health benefits for a population beyond the treatment of primary deficiency syndromes (Krishnaswamy, 1996; Siro et al., 2008; Klement and Kammerer, 2011). In Table 4.1, we list functional foods that already received an FDA-approved health claim, for example, flavonoids, sterols, oats, psyllium, and soy, which are supported by published clinical trials (Hasler et al., 2004; Hasler and Brown, 2009). The level of evidence for health claims varies for different functional foods, that is, the health claim of soy is supported by more than 40 clinical trials, but only a few clinical trials on cranberry juice have been done so far. Although supported by a relatively low number of trials, there is strong scientific evidence for mitigating tumor risk by functional foods such as cruciferous vegetables (Cohen et al., 2003; Abbaoui et al., 2018; Gupta et al., 2010). In normal tissue, cell division cycles are tightly regulated (Fig. 4.4) by positive and negative regulators of the cell cycle. In tumorous tissues, often multiples of these factors are misregulated. Targeting the tumor cell metabolism is an approach commonly utilized to kill tumor cells directly, but indirect methods such as modulating stromal elements like fibroblasts or immune cells are also often used (Athreya and Xavier, 2017). A modification of tumor-specific T cells or an inhibition of crucial metabolic enzymes in cancer tissues is also an efficient method of cancer therapy. So far, numerous anticarcinogens are reported to be naturally present in food or herbs. An effective use of the anticarcinogenic constituents is an important step in preventing cancer. The so-called “designer food” approach is one of the most commonly used approaches where food

Table 4.1

Dietary sources and function of selected functional foods.

Functional foods

Dietary sources

Function

α-Carotene β-Carotene

Yellow-orange and dark-green vegetables Green leafy vegetables and orange and yellow fruits and vegetables Tomatoes, watermelons, apricots, peaches Dark green leafy vegetables Orange fruits Green algae, salmon, trout Salmon, crustacea Brown algae, heterokonts Broccoli, cauliflower, kale Plants Yogurt and fermented foods Soy and phyto-estrogens Rich foods Vegetable and cereals Fish or fish oil

Antioxidant Antioxidant

Lycopene Lutein β-Cryptoxanthin Astaxanthin Canthaxanthin Fucoxanthin Isothiocyanates Flavonoids Probiotics Phyto-estrogens (genistein and daidzein) Fiber Omega-3

Antioxidant Antioxidant Antioxidant Antioxidant Antioxidant Antioxidant Antibacterial Antioxidant Antiallergy Anticancer (breast and prostate) Lowering cholesterol Lowering cholesterol

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FIG. 4.4 A general scheme of cell division in mammalian cells.

FIG. 4.5 Cell cycle regulation in proliferating cells.

ingredients having anticancer potential could be fortified into the regular food or diet (Rajasekaran and Kalaivani, 2013; Kalyanaraman, 2017). Various studies have proved the designer food approach for the prevention of cancer (Fig. 4.5). In recent studies, the administration of bovine milk lactoferrin combined with black tea polyphenols reduced the tumor development of hamster buccal pouch carcinomas by activating carcinogen-metabolizing enzymes and altering the cellular redox status (Chandra Mohan et al., 2005; Vidjaya Letchoumy et al., 2008). Polyphenolic compounds, specifically anthocyanins and flavonoids, are present in red grapes, and are reported to have an inhibitory effect on breast cancer cells under tissue culture conditions (Fang, 2014) (Table 4.2).

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Table 4.2 Molecular targets of dietary agents on cell division cycle regulation in proliferating cells. Nutrient/ botanical

Source

Target cell cycle regulators

References

Grape seed Green tea

Cdk2, Cdk4, Cyclin D1, Cyclin D2, and Cyclin E CKIs (Cip1/p21 and Kip1/p27), Cyclin D1, Cyclin E, Cdk2, Cdk6, caspase DNA synthesis, Cyclin D1, Cyclin E, Cdk4, Cdk7, CKI (Cip1/p21 and Kip1/p27), p53 Cyclin D1, Cyclin D2, Cyclin E; Cdk2, Cdk4, Cdk6; CKI (Cip1/p21 and Kip1/p27) CKI (Cip1/p21 and Kip1/p27), p53 ERK/MAPK NF-kB, STAT

Prieur et al. (1994), Meeran and Katiyar (2007) Gupta et al. (2010), Khan et al. (2006) Liang et al. (2003), Kuwajerwala et al. (2000), Benitez et al. (2007) Li et al. (2005)

Proanthocyanidins (GSP) epigallocatechin3-gallate (EGCG) Resveratrol

Grape

Genistein

Soybean

Curcumin Lycopene Capsiacin

Turmeric Tomato Red chili

luteolin Tangeretin

Vegetables Apple, tangerine Lignans

Sesamin Plumericin Clitocybin B

NF-kB

NF-kB

Liontas and Yeger (2004) Chen et al. (2014a, b) Aggarwal et al. (2009), Kunnumakkara et al. (2018) Jia et al. (2015) Seo et al. (2011) Han et al. (2015) Fakhrudin et al. (2014), Heiss et al. (2016) Moon et al. (2009)

Conclusion Current cancer research is directed toward a better understanding of how functional foods, particularly a specific ingredient, help prevent tumor cell growth (Fig. 4.6). Nutrigenomics, which investigates the interaction between the nutrition, diet, and development of chronic diseases, is based on an individual’s genetic profile. It is going to bring technological breakthroughs and make it feasible to tailor a diet solely based on an individual’s genetic profile (Aggarwal et al., 2009; Landecker, 2011). It is going to affect disease prevention profoundly. Recent advances in biotechnology-derived agriculture are poised to improve the health of millions worldwide. Although functional foods may hold promise for public health, there are concerns that the promotion of functional foods and some functional claims may not rest on sufficiently strong scientific evidence. Any health benefits attributed to functional foods must be based on rigorous scientific studies for safety and efficacy. Interactions with other dietary components and potential adverse interactions with common pharmaceutical agents must be thoroughly studied and communicated to the consumer. Finally, consumers must realize that functional foods are not a “magic bullet” or a panacea for poor eating habits. There are not good and bad foods, only good and bad dietary patterns or practices. Diet is only one aspect of a comprehensive lifestyle approach to good health, which should include regular exercise, tobacco avoidance, stress reduction, maintenance of a healthy body weight, and other positive health practices.

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FIG. 4.6 Nutrients and botanicals that interfere with cell cycle regulators to modulate both normal and tumor cell proliferation.

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Adiponectin-enhancing dietary constituents in cancer prevention Amitabha Raya, Debopam Acharyab a

LAKE ERIE COLLEGE OF OSTEOPATHIC MEDICINE, SE TON HI LL UNI VE RSI TY, GRE ENSBURG, P A, UNITED STATES b DEPART MENT OF ZO OLO GY, JO GAMA YA DEVI COLLEGE, K OLKATA, INDIA

Introduction A growing trend of obesity has been noticed in different parts of the world for nearly 5 decades. The prevalence of overweight or obesity is considered to be a risk factor for various health problems such as hypertension and other cardiovascular diseases, insulin resistance/type 2 diabetes, and different types of cancer. According to the World Health Organization’s report, more than 1.9 billion adults worldwide were overweight or obese in 2016. Similarly, an increasing prevalence of overweight or obesity has been observed among children and adolescents. In general, it is believed that overweight and obesity account for approximately 20% of all cancer cases (Wolin et al., 2010). However, there is considerable geographical variation in the incidence of obesity-related cancers. In the United States in 2014, cancers associated with being overweight and obese constituted 40% of all neoplastic diseases (Steele et al., 2017). On the other hand, in 2010 in Canada, 5.7% of all cancer cases were attributable to excess body weight (Zakaria and Shaw, 2017). Similarly, in France in 2015, 5.3% of all cancer cases were reported to be linked with higher body weight (Arnold et al., 2018). During 2003–2012, excess body weight was responsible for 4.5% of all cancers in Ireland (Collins et al., 2017). In western countries, the prevalence of being overweight and obese has increased markedly over the past decades. For instance, in England, the number of overweight/obese adults increased from 36% to 62% between 1980 and 2013 (Kinlen et al., 2018). Therefore, the burden of obesity-related cancers could be substantial. It is thought that being overweight or obese is associated with cancer risks at various sites, for example, the colon, esophagus (adenocarcinoma), pancreas, gallbladder, kidney (renal cell), endometrium, breast (postmenopausal), prostate (aggressive cases), etc. (Ray et al., 2013). In addition, many studies have reported that excess body weight is usually associated with poor prognosis in cancer patients (Heetun et al., 2018; Lin et al., 2018; Fujita et al., 2019). Perhaps the underlying mechanism for poor prognosis is multifactorial. Apart from therapeutic and surgical complications in obesity, excess Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00005-3 © 2020 Elsevier Inc. All rights reserved.

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adipose tissue may change a tumor’s local environment by a number of mechanisms such as direct interaction between adipose tissue cell populations and cancer cells as well as recruitment and modulation of tumor-associated macrophages and other proin^a et al., 2017). It flammatory immune cells (Fujita et al., 2019; Cozzo et al., 2017; Corre may be worth mentioning that obesity creates a chronic low-grade inflammatory state that also supports pathological conditions such as insulin resistance and metabolic syndrome. A growing body of evidence shows that obesity and associated inflammation can impact the epigenetic regulation of gene expression. In this regard, DNA methylation is a frequently reported epigenetic event. The function may be altered in case of a number of oncogenes such as K-ras, Myc, and Fos (Skrypnik et al., 2017; Dong et al., 2019; Chong et al., 2019). In addition, obesity has been demonstrated to modulate other signaling molecules/pathways, for example, transforming growth factor beta (TGF-β), Wnt/β-catenin, Hedgehog, fat mass- and obesity-associated (FTO) gene product, AKT, and fatty acid synthase (FASN), which are also involved in the pathological processes of cancer (Chong et al., 2019; Sousa-Pinto et al., 2016; Debebe et al., 2017; Liao et al., 2018; Chen and Du, 2019). A xenograft study showed that tumors derived from the HER2-overexpressing MCNeuA mouse carcinoma cell line had high low-density lipoprotein (LDL) receptor expression and formed larger tumors in mice with high circulating LDL-cholesterol (LDL-C) concentrations than in mice with lower LDL-C (Gallagher et al., 2017). Of note, overexpression of the HER2 oncogene is involved in cancer prognosis and elevated LDL-C is frequently seen in obesity. Nevertheless, HER2 has been shown to be associated with a number of aforesaid molecules such as FASN, FTO, and AKT (Vazquez-Martin et al., 2008; Tan et al., 2015; Ray, 2017). Apart from the alteration in the gene expression pattern in obesity, normally adipose tissue is involved in numerous biological phenomena such as insulation, mechanical support, and energy storage. Contrary to our previous view, it is now accepted that the adipose tissue is not an inert tissue. In fact, adipose tissue functions as an endocrine organ and secretes various hormone-like cytokines that are known as adipocytokines or adipokines. In an environment of obesity, the majority of these adipokines have proinflammatory functions (Table 5.1). It may be worth mentioning that in obesity-induced insulin resistance, these proinflammatory adipokines perhaps affect the pathogenesis immensely. Nevertheless, these adipokines play a vital role in our metabolism and energy homeostasis. On the other hand, there are few antiinflammatory adipokines such as adiponectin, secreted frizzled-related protein 5 (SFRP5), and omentin. Among these antiinflammatory adipokines, the functions of adiponectin have been widely studied in both epidemiological/clinical and experimental settings. This review is an attempt to identify different dietary components, particularly omega-3 polyunsaturated fatty acids (ω-3 PUFA), that may increase the levels of adiponectin in our body.

Chapter 5 • Adiponectin-enhancing dietary constituents in cancer prevention

Table 5.1

A few proinflammatory adipokines and their main characteristics.

Important adipokines Leptin

Interleukin-6 (IL-6)

Monocyte chemoattractant protein-1 (MCP-1)

Resistin

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Biological features

Role in pathological state

It is a product of ob gene on chromosome 7 and is comprised of 146 amino acids. The amount of circulatory leptin is positively correlated with the quantity of white adipose tissue. Leptin functions via its receptors (Ob-R), which are present on the cell surface. There are at least six isoforms of Ob-R; the long transmembrane isoform Ob-Rb is important in energy homeostasis and possibly for leptin’s proinflammatory effects. The principal intracellular signaling pathway for Ob-R is the JAK2-STAT3 pathway. However, leptin is also associated with other signaling pathways such as phosphatidylinositol 3-kinase (PI3K) and mitogenactivated protein kinase (MAPK). Leptin is an anorexigenic hormone and controls satiety through its action in the hypothalamus IL-6 is a pleiotropic cytokine produced by a variety of cell types including monocytes and macrophages. However, adipose tissue is also a significant source. The IL-6 receptor complex consists of the ligand-binding chain (transmembrane and soluble IL-6R) and the signaltransducing chain (gp130). Finally, the signaling through gp130 results in the activation of downstream JAK-STAT and MAPK pathways Monocyte chemoattractant protein-1 (MCP-1/ CCL2) is an important chemokine, which functions primarily in the process of celltrafficking, and regulates migration and infiltration of monocytes/macrophages. Human MCP-1 is composed of 76 amino acids and the gene is located on chromosome 17. MCP-1 is secreted by a variety of cell types, including monocyte/macrophages, endothelial cells, and adipocytes. This chemokine mediates its effects through its receptors (CCR2), which are present in two forms—CCR2A and CCR2B Initially, resistin was found to be secreted from adipose tissue and involved in insulin resistance. Nevertheless, in human subjects, resistin is mainly produced by nonadipose tissue cells such as macrophages and bone marrow cells. Human resistin consists of 108 amino acids and the gene is located on chromosome 19. In circulation, different low and high molecular weight isoforms (oligomers) are found

Apart from mutations in the leptin (ob) and/ or Ob-R (db) genes, leptin resistance (i.e., a decrease in tissue sensitivity to leptin along with hyperleptinaemia) is closely associated with obesity. Therefore, leptin resistance also has a close connection with pathological conditions such as insulin resistance, dyslipidemia, and metabolic syndrome. Among a number of proposed mechanisms, a chronic low-grade inflammatory state in obesity perhaps supports the development of leptin resistance. Elevated levels of leptin have been demonstrated to be linked with an increased risk of different cancers IL-6 plays a key role in various inflammatory states and cancers. In normal condition, through activation of hematological, immune, and acute-phase responses, IL-6 supports in the healing process/tissue regeneration. Therefore, this cytokine has significant functions in both health and pathological conditions Primarily the function of MCP-1 is inflammatory response and it controls the recruitment of leukocytes in the sites of inflammation and tissue injury. MCP-1 has been demonstrated to be involved in various diseases such as AIDS, atherosclerosis, and different types of cancer

Resistin perhaps plays an important role in several obesity-related disorders, for example, insulin resistance/diabetes, atherosclerosis, coronary artery disease, nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, and cancer

Continued

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Table 5.1 Important adipokines Tumor necrosis factor alpha (TNF-α)

Visfatin

A few proinflammatory adipokines and their main characteristics—cont’d Biological features

Role in pathological state

TNF-α is mainly produced by immune cells; however, other sources such as endothelial cells, neurons, and adipocytes also produce this cytokine. The gene is located on chromosome 6. TNF-α has two forms: the membrane bound and secreted forms, and two distinct receptors: TNF-RI and TNF-RII. From cells, these two receptors can be released and thus soluble forms are generated. Both receptors can activate a variety of signaling molecules, for example, MPAK, extracellularsignal-regulated kinases (ERK), c-jun N-terminal kinase (JNK), and nuclear factor NF-κB Visfatin is also known as pre-B cell colonyenhancing factor (PBEF) or nicotinamide phosphoribosyltransferase (NAMPT) and produced primarily by the visceral adipose tissue. This adipokine consists of 491 amino acids and the gene is located on chromosome 7. Visfatin has both an intracellular enzymatic activity and cytokine function. By binding to the insulin receptor (insulin-mimetic effects), visfatin reduces blood glucose. Moreover, it can induce the production of TNF-α and IL-6

Physiological functions of TNF-α include participation in immune reactions and induction of apoptosis. On the other hand, TNF-α may induce insulin resistance, allergies, and systemic inflammation

Blood levels of visfatin are elevated in obesity, insulin resistance/type 2 diabetes, and metabolic syndrome. Apart from the above-mentioned conditions, possibly visfatin is also involved in the relevant disorders, for example, dyslipidemia, hypertension, endothelial dysfunction, and renal failure

Inflammation in carcinogenesis Evidence shows that there is a connection between chronic inflammation and the risk of cancer development. It is estimated that infection and inflammation account for approximately 25% of cancer-causing factors (Murata, 2018). Infectious agents have been demonstrated to increase cancer risk through chronic inflammation. For example, organisms such as Schistosoma haematobium, Helicobacter pylori, and human papillomavirus are associated with the risk of carcinogenesis. Similarly, other inflammatory risk factors such as the use of tobacco and/or alcohol and asbestos exposure can increase the risk for a number of cancers. In the case of pancreatic cancer, inflammation plays a significant role in different phases, namely in initiation, progression, and metastasis. Many known risk factors for pancreatic cancer, including alcohol consumption, cigarette smoking, diabetes, and chronic pancreatitis, are often characterized by the induction of chronic inflammation (Shi and Xue, 2019). In addition, the hepatocellular carcinoma is connected with chronic inflammation arising from various etiopathologic factors, including hepatitis B and C as well as alcoholic and nonalcoholic fatty liver diseases (Yang et al., 2019). On the other hand, gut bacteria play a crucial role in intestinal homeostasis but can also contribute to chronic inflammation and cancer (Chen, 2018). In skin cancer, the

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ultraviolet radiation induces several biological effects such as DNA damage and reactive oxygen species (ROS) generation. These alterations can induce inflammation and initiate tumorigenesis (Neagu et al., 2019). Chronic inflammation can promote carcinogenesis, and solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination (Munn, 2017). Under chronic inflammation, ROS from inflammation increases oxidative stress and damages DNA and other biomolecules. Furthermore, chronic inflammation may cause epigenetic aberrations such as DNA methylation and microRNA dysregulation, which play vital roles in carcinogenesis (Murata, 2018). In obesity, chronic inflammation is promoted by adipose tissue dysfunction along with excess nutrients that lead to the activation of metabolic signaling pathways, including phosphatidylinositol 3-kinase (PI3K), Janus kinase (JAK), signal transducer and activator of transcription (STAT), c-Jun N-terminal kinase (JNK), and nuclear factor κB (NFκB) (Goodwin and Stambolic, 2015; Kolb et al., 2016). The activation of these pathways leads to the induction of a low level of inflammatory cytokines/adipokines resulting in a low-grade inflammatory response. A proinflammatory signal engages and stimulates neutrophils and macrophages, and in turn, ROS is created. Therefore, oxidative stress and inflammation, which commonly occur in obesity, can cause DNA damage and promote cancer growth (Włodarczyk and Nowicka, 2019). On the other hand, hypertrophic/dysfunctional adipose tissue-released abnormal levels of adipokines mediate cancer progression through a variety of other pathological mechanisms such as angiogenesis, cell proliferation, and evasion of apoptosis. Recently, a number of studies on obesity and/or associated pathologies have observed a conflicting relationship between two important adipokines: proinflammatory leptin and antiinflammatory adiponectin (Table 5.2). In general, obesity and its relevant disorders such as insulin resistance and metabolic syndrome are associated with an increase in blood leptin levels and a concurrent decrease in blood levels of adiponectin. Therefore, the relative proportion of these two adipokines in blood perhaps indicates a state of dysfunctional adipose tissue. Although leptin normally plays an important role in the hypothalamus to regulate our food intake and satiety, it behaves differently in an obese condition. As mentioned earlier, leptin supports a proinflammatory environment in obesity. Furthermore, a growing body of evidence suggests that leptin could influence cancer development and progression through a number of biological phenomena, for example, oxidative stress, recruitment of inflammatory cells, angiogenesis, cell proliferation, and evasion of apoptosis (Ray et al., 2007; Mahbouli et al., 2017; Ray and Cleary, 2017).

Antiinflammatory adiponectin and allied compounds Unlike leptin, adiponectin perhaps has a protective role against tumor development. Recently, a considerable number of reports have demonstrated that cancer patients usually had significantly lower blood levels of adiponectin (Table 5.3).

Study type/description

Findings in brief

Ashktorab et al. (2018)/United States Berstein et al. (2015)/Russia

Case-control study: 180 African-American patients with colon adenoma and 198 healthy African-Americans (controls)

There was a negative correlation between serum adiponectin and leptin concentrations with BMI

258 endometrial cancer patients were divided into two groups: women with obesity and metabolically healthy obese women

Chandar et al. (2015)/Metaanalysis

Nine observational studies (1432 patients with Barrett’s esophagus and 3550 control subjects)

de Martino et al. (2016)/ Austria Di Sebastiano et al. (2017)/ Canada Gupta et al. (2017)/India

131 patients with sporadic unilateral renal cell carcinoma

Endometrial cancer patients with obesity often displayed a higher serum leptin/adiponectin ratio compared with metabolically healthy obese group High serum level of leptin was associated with two-fold higher risk of Barrett’s esophagus. Total serum level of adiponectin was not associated with Barrett’s esophagus, although one study observed decreased risk of Barrett’s esophagus with increased level of lowmolecular-weight adiponectin Serum adiponectin was lower in patients with distant metastasis. However, leptin levels were not associated with either renal cell carcinoma pathology or outcomes Men with higher Gleason scores had significantly greater leptin concentrations and leptin:adiponectin ratio than those with lower Gleason scores Leptin and leptin:adiponectin ratio were significantly higher in PCOS women compared to non-PCOS. Leptin:adiponectin ratio was significantly high in PCOS with metabolic syndrome compared to without metabolic syndrome, and adiponectin levels were significantly low Obese patients with prostate cancer had a higher incidence of tumors with a high Gleason score and extraprostatic extension than patients with a normal BMI. Patients with obesity showed significantly lower serum adiponectin and higher serum leptin levels Leptin-to-adiponectin ratio was significantly higher in cancer group compared with benign hyperplasia group. In the poorly differentiated cancer subgroup, patients had higher serum leptin concentrations A positive correlation was found between leptin concentration and BMI. The leptin/adiponectin ratio before treatment correlated with better response to chemotherapy Adiponectin was significantly associated with decreased risk of cancer, and leptin was significantly associated with increased risk of cancer. Higher level of adiponectin was associated with decreased risk of breast, colorectal, and endometrial cancer. Higher leptin was associated with increased risk of endometrial and kidney cancer

51 men were evaluated prior to prostate biopsy

Case-control study: 439 female subjects in two groups—Patients with polycystic ovary syndrome (PCOS) (n ¼ 223) and control women (non-PCOS) (n ¼ 216). Further, both groups were subdivided in two—women with or without metabolic syndrome

Kang et al. (2018)/South Korea

Two groups of patients with localized prostate cancer according to their BMI: nonobese (n ¼ 25) and obese (n ¼ 37)

 ska et al. Siemin (2018)/Poland

Patients with prostate cancer (n ¼ 74) and benign prostatic hyperplasia (n ¼ 66)

Słomian et al. (2019)/Poland

43 ovarian cancer patients—blood levels of adiponectin and leptin were measured before and after chemotherapy

Yoon et al. (2019)/Metaanalysis

93 observational studies were included

BMI, body mass index; PCOS, polycystic ovary syndrome.

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Table 5.2 Selected recent studies on the status of circulating adiponectin and leptin levels in various cancers and relevant health disorders.

Chapter 5 • Adiponectin-enhancing dietary constituents in cancer prevention

Table 5.3 Site of malignancy Blood cell

Breast

Cancers of different sites

Colon

Endometrium

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Status of adiponectin concentrations in various neoplastic conditions. Investigators and study characteristics

Findings in brief

Hofmann et al. (2016) 624 multiple myeloma cases and 1246 matched controls from 7 cohorts Hofmann et al. (2017) Circulating adiponectin levels were measured in patients with multiple myeloma (n ¼ 25) and precursor conditions—smoldering multiple myeloma (n ¼ 104) and monoclonal gammopathy of undetermined significance (n ¼ 84) (United States) Ma et al. (2016) Meta-analysis: 11 studies—637 leukemia patients and 524 controls Agnoli et al. (2017) A case-control study within the EPIC-Varese cohort (nested within 9378 women). After a median 14.9 years, 351 breast cancer cases were identified and matched to 351 controls (Italy) Gu et al. (2018) Meta-analysis: 31 studies were included (7388 cases and 8491 controls) Gui et al. (2017) Meta-analysis: 119 studies were selected € ven et al. (2018) Gu In 83 patients, serum adiponectin levels were measured preoperatively and subsequent followup (Turkey) Yu et al. (2019) Meta-analysis: 27 case-control studies (7176 cases and 8318 controls) Wei et al. (2016) Meta-analysis: 107 studies were included (broadly 17 different cancers) with 19319 cases and 25675 controls Huang et al. (2018) In vitro study

Higher total adiponectin levels were associated with reduced multiple myeloma risk

Lu et al. (2018) Meta-analysis: 48 studies (7554 patients and 9798 controls) Wang et al. (2019) A retrospective case-control study of 53 patients and 98 healthy women as the control group (China)

Relative to patients with monoclonal gammopathy of undetermined significance, adiponectin levels were significantly lower among patients with smoldering and fully developed multiple myeloma

Serum adiponectin levels of patients with leukemia were lower than healthy controls Among postmenopausal women, high blood adiponectin was significantly associated with reduced risk

Serum adiponectin levels in breast cancer cases were significantly lower than the control group Decreased concentrations of adiponectin were significantly associated with breast cancer risk Adiponectin levels tended to be significantly lower as the stage of the disease increased. Levels of adiponectin above 15,300 ng/mL were associated with improved disease-free survival Overall, there was an inverse association between serum adiponectin levels and breast cancer Circulating adiponectin levels were lower in patients with various cancers than in controls

Adiponectin inhibited the proliferation of colorectal cancer HCT116 cells, induced cell arrest at G1/G0 phase, and promoted apoptosis Circulating total adiponectin levels, especially non-HMW fraction, were significantly lower in patients with colorectal cancer than in controls Serum adiponectin level in the endometrial cancer group was significantly lower than in the control group Continued

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Table 5.3 cont’d Site of malignancy Kidney

Lung

Status of adiponectin concentrations in various neoplastic conditions—

Investigators and study characteristics

Findings in brief

de Martino et al. (2016) 131 patients with sporadic unilateral renal cell carcinoma (Austria)

Adiponectin was lower in patients with distant metastases. Each 1-μg/mL increase in adiponectin was associated with an 8% decrease in the hazard of death from cancer Serum adiponectin levels were lower in clear cell renal cell carcinoma patients than in patients with other histological types

Wang et al. (2016a) 156 patients had clear cell renal cell carcinoma and 42 patients had other subtypes of renal cell carcinoma (China) Cui et al. (2018) In vitro study

Nigro et al. (2019) In vitro study

Ovary

Hoffmann et al. (2018) In vitro study

Pancreas

Jiang et al. (2019) In vitro study

Prostate

Nogueira et al. (2017) A pooled nested case-control analysis in 3 cohorts with 758 cases and 1052 controls (United States) Angel et al. (2019) Meta-analysis: 35 studies were eligible for inclusion

Adiponectin significantly impaired the migratory and invasive capacities of nonsmall cell lung carcinoma cells (NCI-H1299, HCC827 and A549) through reversal of epithelial-mesenchymal transition On human lung adenocarcinoma A549 cells, adiponectin caused, in a time- and dosedependent manner, a reduction of cell viability and duplication (i.e., proliferation) together with an increase in cell apoptosis rate Adiponectin inhibited the growth of OVCAR-3 and SKOV-3 epithelial ovarian cancer cells. Moreover, adiponectin reversed the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation Adiponectin treatment significantly inhibited the proliferation of BxPC-3 and CFPAC-1 human pancreatic cancer cells High molecular weight adiponectin was inversely associated with pancreatic ductal adenocarcinoma in never smokers Several cohorts reported decreased adiponectin levels in men who later developed advanced prostate cancer

As previously stated, adiponectin is primarily secreted by adipocytes and it has an antiinflammatory property. In blood, different isoforms of adiponectin are present such as the low molecular weight form (LMW, union of three monomeric molecules or trimer), the middle molecular weight (MMW, hexamer) form, and the high molecular weight (HMW) form (Fig. 5.1). It is believed that the HMW isoform is the most biologically active adiponectin, which promotes glucose uptake, insulin sensitivity, and fatty acid oxidation (van Andel et al., 2018). Biological functions of adiponectin are mediated through three different receptors:

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FIG. 5.1 Adiponectin’s different isoforms (A) and receptors (B). C1q, subcomponent of complement 1 complex; COOH, carboxyl-terminus; ECM, extracellular matrix; HMW, high molecular weight adiponectin; LMW, low molecular weight adiponectin; MMW, middle molecular weight adiponectin; NH2, amino-terminus.

classical AdipoR1 and AdipoR2 transmembrane receptors and T-cadherin that lacks transmembrane and cytoplasmic domains. Regarding the intracellular signaling pathways, the effects of adiponectin are primarily mediated via AMP-activated protein kinase (AMPK, a central regulator of energy homeostasis), mechanistic/mammalian target of rapamycin (mTOR, a serine/threonine kinase that controls cell growth and metabolism), PI3K/ AKT, mitogen-activated protein kinase (MAPK), STAT3, and NF-κB (Di Zazzo et al., 2019). In general, adiponectin induces the activation of AMPK. On the contrary, adiponectin has inhibitory effects on the pathways of different signaling molecules, for example, PI3K, AKT, mTOR, STAT3, and NF-κB, which are involved in a number of biological events such as inflammation, cell proliferation, and survival. Considering the antiinflammatory and insulin-sensitizing effects of adiponectin, enhancement of adiponectin biosynthesis by different dietary/herbal components is possibly a promising concept (Table 5.4). Alternatively, adiponectin receptor agonists could be a fascinating area to simulate adiponectin-like functions. It is interesting to note that osmotin, a plant protein, has been shown to activate AMPK via an adiponectin receptor (AdipoR), like adiponectin (Narasimhan et al., 2005). Osmotin is a 26-kDa protein and belongs to the pathogenesis-related (PR)-5 family; it is involved in plant defense responses to several pathogens and abiotic stresses (Viktorova et al., 2012; Anil Kumar et al., 2015). Fruits and vegetables such as grapes, tomatoes, soybeans, and carrots are good sources of osmotin (Murthy et al., 2009).

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Table 5.4 Salient findings of different in vitro, in vivo, and epidemiological/clinical studies that showed modulation of adiponectin expression or its circulating levels by various herbal or food constituents. Dietary or herbal components (Sourcea) and Authors Ac¸aı´ (Euterpe oleracea Mart.) seed extract with exercise (Brazil) (de Bem et al., 2018) Allium fistulosum (Welsh onion) ethanolic extract (Sung et al., 2018) Argan oil from Argania spinosa (Morocco) (El Midaoui et al., 2017) Baccharis halimifolia (groundsel bush)—ethanolic extract (United States) (Boudreau et al., 2018) Bergamottin (from grapefruit juice) (Ko et al., 2018) Berry meals (included four different berries) (Lehtonen et al., 2010) β-conglycinin (soy protein) (Tachibana et al., 2014) Bitter melon/bitter gourd (Momordica charantia) extract (Chao et al., 2011) Bushenkangshuai herbal compound (China) (Pang et al., 2018) Chitosan oligosaccharide (China) (Pan et al., 2018) Chokeberry extract (Qin and Anderson, 2012) Chrysanthemum indicum L. flowers—extract (Asia) (Cha et al., 2018)

Experimental design

Findings in brief

Diabetic complications were induced by high-fat diet plus streptozotocin in male Wistar rats. Extract by gavage and exercise for 4 weeks after diabetes induction Male C57BL/6J mice—treatment for 6 weeks

Ac¸aı´ seed extract associated with exercise training potentiated the expression of adiponectin in adipose tissue

3T3-L1 preadipocytes (in vitro study)

In both differentiating and mature adipocytes, adiponectin was found to be increased by the extract of groundsel bush

3T3-L1 preadipocytes (in vitro study)

The expression of adiponectin was decreased by bergamottin

Serum adiponectin levels were improved in high-fat diet fed mice treated with fistulosum ethanolic extract Male Sprague-Dawley rats—treatment for There was an induction in plasma 12 weeks adiponectin levels by argan oil

Female volunteers: berry group (n ¼ 28) In the berry group, plasma adiponectin and control group (n ¼ 22)—dietary increased intervention for 20 weeks Spontaneously diabetic Goto-Kakizaki rats Plasma adiponectin levels and AdipoR1 RNA expression in skeletal muscle were higher in β-conglycinin fed rats C57BL/6J mice—administered for 2 weeks Significantly higher plasma adiponectin level in bitter gourd group

ApoE/ mice—treatment for 6 weeks

On Sprague-Dawley rats with obesity induced by a high-fat diet—8 weeks administration Male Wistar rats were fed a fructose-rich diet and chokeberry extract for 6 weeks Male C57BL/6J mice with high-fat dietinduced obesity—administered for 6 weeks

Bushenkangshuai promoted the expression of adiponectin and its receptors in atherosclerotic aorta and increased the serum levels of adiponectin Increased expression of liver adiponectin was observed Chokeberry extract consumption elevated plasma adiponectin levels Oral administration increased serum adiponectin levels

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Table 5.4 Salient findings of different in vitro, in vivo, and epidemiological/clinical studies that showed modulation of adiponectin expression or its circulating levels by various herbal or food constituents—cont’d Dietary or herbal components (Source) and Authors Cissus quadrangularis— aqueous leaf and stem extract (Tropical and subtropical zone) (Nash et al., 2019) Coffee (Hang et al., 2019)

Cranberry juice (low-energy) (Sima˜o et al., 2013) Curcumin (from turmeric) (Adibian et al., 2019) Dibenzoylmethane (from licorice roots) (Kim et al., 2018) Dioscoreophyllum cumminsii (tropical rainforest vine)—leaf extract (Ibitoye et al., 2017) Erigeron annuus extract (Choi et al., 2019) Euphorbia supina—ethanol extract (Korea) (Nepali et al., 2018) Fenugreek (Trigonella foenumgraecum) seeds—aqueous extract (Kumar et al., 2014) Fiber intake (AlEssa et al., 2016) Gallic acid (Makihara et al., 2016) Grape powder (Barona et al., 2012)

Experimental design

Findings in brief

Placebo group (32 individuals) and extract There was a significant increase in group (35 individuals)—8 weeks of blood levels of adiponectin among extract treatment group compared with the placebo group Cohorts of 15551 women (Nurses’ Health Compared with nondrinkers, participants Study) and 7397 men (Health Professionals who drank 4 cups of total coffee/day had Follow-Up Study) higher plasma concentrations of total adiponectin and HMW adiponectin 56 individuals with metabolic syndrome— Cranberry-treated group showed an consumption for 60 days increase in serum adiponectin 44 patients with type 2 diabetes The mean serum concentration of adiponectin was increased in the treatment group compared with the placebo 3T3-L1 preadipocytes (in vitro study) Dibenzoylmethane effectively increased adiponectin in adipocytes Male albino rats of Wistar strain—high-fat The treatment increased the serum levels diet and leaf extract for 4 weeks of adiponectin

3T3-L1 preadipocytes (in vitro study) Male C57BL/6J mice—administered for 6 weeks

E. annuus extract upregulated adiponectin expression E. supina extract increased serum adiponectin levels

Female Wistar rats were fed with high fat Treatment with fenugreek seed extract produced significant elevation in diet and seed extract for 4 weeks adiponectin levels Cross-sectional analysis of 2458 diabetes- Total dietary fiber intake and a lower free women in the Nurses’ Health Study starch-to-fiber intake ratio were positively associated with adiponectin blood levels 3T3-L1 preadipocytes (in vitro study) Gallic acid enhanced the expression and secretion of adiponectin 24 men with metabolic syndrome (13 Plasma adiponectin was increased in grape without dyslipidemia)—consumption for consumption participants compared to placebo, only in individuals without 4 weeks dyslipidemia Continued

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Table 5.4 Salient findings of different in vitro, in vivo, and epidemiological/clinical studies that showed modulation of adiponectin expression or its circulating levels by various herbal or food constituents—cont’d Dietary or herbal components (Source) and Authors

Experimental design

Green tea (Camellia sinensis L.) 120 healthy subjects—for 12 weeks (Maeda-Yamamoto et al., 2018) Honeysuckle anthocyanins High-fat diet-induced obese C57BL/6 (Wu et al., 2013) mice—treatment for 8 weeks Isoflavones (Charles et al., 2009)

75 healthy postmenopausal women— received for 12 weeks

Laminaria japonica (Korean zone) (Kim and Jang, 2018) Large yellow tea (China) (Xu et al., 2018) Loganic acid, extracted from Gentiana lutea L. root (Korea) (Park et al., 2018) Monolluma quadrangula— hydroethanolic extract (Middle East) (Bin-Jumah, 2019) Mulberry (Morus alba) leaf extract (Peng et al., 2018) Olive oil—extra-virgin (Luque-Sierra et al., 2018) Pistachio nuts (Gulati et al., 2014) Procyanidins (flavonoids) (Chaco´n et al., 2009)

3T3-L1 preadipocytes (in vitro study)

Raspberry ketones (Mehanna et al., 2018) Soy milk—fermented with Lactobacillus plantarum (Kim et al., 2014)

C57BL/6 male mice—treatment for 12 weeks 3T3-L1 preadipocytes (in vitro study)

Findings in brief Tea ingestion significantly increased serum adiponectin levels Honeysuckle anthocyanins significantly increased serum adiponectin concentration Serum adiponectin levels increased in women taking high-dose isoflavones compared to placebo L. japonica fermentation extract decreased the concentration of adiponectin Large yellow tea raised serum adiponectin levels The expression of the adiponectin gene was significantly reduced following treatment with loganic acid

Male Wistar rats—diabetes was induced by Increased serum adiponectin levels and feeding a high-fat diet and streptozotocin; hepatic adiponectin expression by quadrangula extract for 4 weeks M. quadrangula Male Wistar rats—treatment for 14 weeks Mulberry leaf extract increased the plasma level of adiponectin Ldlr/.Leiden mice with high-fat diets

Olive oil group exhibited the greatest levels of adiponectin in adipose tissue Significant improvement of adiponectin levels in the pistachio group Procyanidins enhanced the production of adiponectin

60 individuals with the metabolic syndrome—24 weeks trial Human adipocytes (SGBS) and macrophage-like (THP-1) cell lines— administration of an extract of grape-seed procyanidins High-fat diet-fed male rats Administration upregulated adipose tissue expression of adiponectin compared to high-fat diet control rats Male Sprague-Dawley rats—treatment for Fermented soy milk elevated adipose tissue 6 weeks expression levels of adiponectin and its receptors

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Table 5.4 Salient findings of different in vitro, in vivo, and epidemiological/clinical studies that showed modulation of adiponectin expression or its circulating levels by various herbal or food constituents—cont’d Dietary or herbal components (Source) and Authors Taiwanese green propolis ethanol extract (Chen et al., 2018) Tomato powder (Li et al., 2018)

Experimental design

Findings in brief

Streptozotocin/high-fat diet-induced (Sprague-Dawley) rat model

There were higher levels of adiponectin in the serum of the treated group

BCO1//BCO2/ double knockout mice were fed a high fat diet—tomato powder feeding for 24 weeks Hypercholesterolemic Wistar rats

Tomato powder feeding was associated with increased plasma adiponectin and hepatic adiponectin receptor-2 (AdipoR2) Supplementation resulted in significant increase in serum adiponectin levels

Tripodanthus acutifolius leaves—hydroalcoholic extract (Coelho et al., 2018) Vernonia cinerea water extract High-fat diet-induced obese mice— (Southeast Asia) treatment with extract for 6 weeks (Naowaboot et al., 2018) a

Increased serum adiponectin level in obese mice treated with V. cinerea

The place where the species grows naturally.

A recent study has noticed that osmotin caused cell cycle arrest in the G0/G1 phase by regulating the expression of cell cycle regulators p21, p27, and cyclin-dependent kinase 2 (CDK2) in the 3T3-L1 adipocyte cell line ( Jo et al., 2019). The study also revealed the role of osmotin in AMPK downstream signaling. On the other hand, Takahashi et al. (2018) observed that osmotin exerted preventive effects on vascular inflammation and atherosclerosis. In a model of myocardial ischemia/reperfusion, osmotin has been shown to increase the viability of rat cardiac myoblast H9c2 cells (Liu et al., 2017). In addition, osmotin reduced the release of proinflammatory factors and increased the release of antiinflammatory factors in this cell line. Using a different model of inflammation, Arsenescu et al. (2011) found that osmotin, like adiponectin, improved the colitis outcome in C57BL/ 6 mice with dextran sulfate sodium (DSS)-induced colitis. Among experiments on cancer cells, it has been documented that osmotin decreased the proliferation of TRAMP-C2 mouse prostate cancer cells in a manner very similar to adiponectin (Grossmann et al., 2009). In another study, osmotin has been reported to stimulate adiponectin receptors and related downstream pathways in human liver carcinoma HepG2 cells exposed to palmitic acid (Ahmad et al., 2019). Overall, the activation of the downstream components of the adiponectin signaling pathway such as peroxisome proliferator-activated receptor alpha (PPAR-α), AMPK, and Sirtuin 1 (SIRT1) is linked to several improved health conditions, for example, reduced body weight, better glucose tolerance, diminished insulin resistance, and increased fatty acid oxidation. There is a close association between adiponectin and peroxisome proliferatoractivated receptors (PPARs). It may be worth mentioning that PPARs are ligand-activated

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transcription factors of the nuclear hormone receptor superfamily and have three subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ. Although their functions are intricate, PPAR-α is thought to play a key role in hepatic fatty acid oxidation as well as in the lipid and lipoprotein metabolism. Furthermore, activation of PPAR-γ causes insulin sensitization and enhances the glucose metabolism while PPAR-β/δ promotes the fatty acid metabolism (Tyagi et al., 2011). Interestingly, PPAR-γ upregulates adiponectin levels along with HMW adiponectin and PPAR-α upregulates AdipoRs (van Andel et al., 2018; Yamauchi and Kadowaki, 2008; Giby and Ajith, 2014). Moreover, adiponectin can increase PPAR-γ in adipose tissue (Giby and Ajith, 2014). Conversely, PPAR-γ activation promotes AdipoR2, which also induces the activation of PPAR-γ and PPAR-α (van Andel et al., 2018; Polvani et al., 2016). For this reason, dual activation of PPAR-γ and PPAR-α improves the action of adiponectin by increasing both total and HMW adiponectin and AdipoRs, which can result in the amelioration of obesity-induced inflammation and insulin resistance (Yamauchi and Kadowaki, 2008). Therefore, the modulation of adiponectin biosynthesis could be a promising strategy for the prevention of different obesity-related diseases, including cancer. In fact, pharmaceutical agents such as PPARγ agonist thiazolidinediones and PPAR-α agonist fibrates can increase the production of adiponectin (Matsuda et al., 2014; Matsuda and Shimomura, 2014). On the other hand, many studies have demonstrated that polyunsaturated fatty acids (PUFAs), € hl especially omega-3 PUFAs, are able to induce the biosynthesis of adiponectin (Ru and Landrier, 2016). Interestingly, PUFAs are known agonists of PPARs.

Omega-3 PUFAs and adiponectin PUFAs can be classified into ω-3 (omega-3 or n-3) and ω-6 (omega-6 or n-6) categories owing to their location of the first double bond from the methyl end of the fatty acid chain (Fig. 5.2). The beneficial health effects in humans are mainly contributed by two members of the omega-3 fatty acid family: long-chain eicosapentaenoic acid (EPA) and very-long-chain docosahexaenoic acid (DHA), the major elongation and desaturation product of α-linolenic acid (ALA). The major dietary sources of ALA include seeds or their oils such as canola, flaxseed, and chia seeds, and green leafy vegetables such as kale and spinach (Rajaram, 2014). On the other hand, good sources of dietary long-chain and very-longchain omega-3 PUFAs are marine fish and fish oil that supply EPA and DHA (Ulven and Holven, 2015). Nevertheless, the favorable effects of omega-3 PUFAs on human health have been known since the 1970s. Since then, continued research has revealed useful effects of omega-3 fatty acids in a variety of human health problems, including cancers (Riediger et al., 2009). Delayed onset of tumors, growth inhibition, and the death of cancer cells by omega-3 fatty acids have been shown in both in vitro and in vivo experiments (Azrad et al., 2013; Zheng et al., 2014; Liang et al., 2016). In general, the intake of omega-3 has been demonstrated to increase circulating adiponectin concentrations. For instance, in a recent meta-analysis, the authors showed that

Chapter 5 • Adiponectin-enhancing dietary constituents in cancer prevention

ω-6 PUFA Soybean oil Corn oil Safflower oil Olive oil Sunflower oils Whole-grain breads Baked foods Margarine

ω-3 PUFA O OH

H3C

In plants

Linolenic acid (LA, C18:2, n-6) FADS2, Δ6-desaturase

ELOV5, elongase

Δ17-desaturase

FADS1, Δ5-desaturase

Δ17-desaturase

Arachidonic acid (AA, C20:4, n-6)

O OH

H3C

a-linolenic acid (ALA, C18:2, n-3)

Δ17-desaturase

g-linolenic acid (GLA, C18:3, n-6)

dihomo-g-linolenic acid (DGLA, C20:3, n-6)

Meat Egg yolk Dairy

Δ15-desaturase

87

FADS2, Δ6-desaturase

Stearidonic acid (SDA, C18:4, n-3)

Flax seed oil Canola oil Walnut Green leafy vegetables

ELOV5, elongase

Eicosatetraenoic acid (ETA, C20:4, n-3) FADS1, Δ5-desaturase

Eicosapentaenoic acid (EPA, C20:5, n-3) ELOV5, elongase

Docosapentaenoic acid (DPA, C22:5, n-3) ELOV2, elongase

Tetracosanolpentaenoic acid (C24:5, n-3) FADS2, Δ6-desaturase Released from cell membrane by cytosolic phospholipase A2 (cPLA2)

Retro conversion

Prostaglandins series 2 (PGA2, PGE2, PGI2, TXA2)

EPA

Docosahexaenoic acid (DHA; C22:6, n-3)

5-LOX Resolvins, D series (RvD1 and RvD2)

Leukotrienes series 4 (LTB4, LTC4, and LTE4)

COX-2 Pro-inflammation Angiogenesis Cancer growth

Mackerel Tuna Trout Herring Sardines Salmon

β-oxidation

AA

COX-2

Tetracosahexaenoic acid (THA; C24:6, n-3)

Marine fishes

Prostaglandins series 3 (PGB3, PGD3, PGE3, PGI3, TXA3)

5-LOX Leukotrienes series 5 (LTB5, LTC5, and LTD6)

Resolvins, E series (RvE1 and RvE2)

Anti-inflammatoin Apoptosis Cancer inhibition

FIG. 5.2 Dietary source and metabolism of omega-3 and omega-6 PUFAs and biosynthesis of eicosanoids. PUFAs, polyunsaturated fatty acids; Eicosanoids: signaling lipids derived from arachidonic acid or associated PUFAs.

supplementation of omega-3 fatty acids increased adiponectin levels (Becic and Studenik, 2018). The analysis included 14 studies and 685 individuals. On the other hand, a 12-week interventional study among 201 healthy middle-aged volunteers observed an enhanced serum adiponectin level with the consumption of fish oil (Song et al., 2018). Furthermore, in a cross-sectional study, serum HMV adiponectin was measured in 170 subjects (TorresCastillo et al., 2018). The investigators found that a high dietary omega-6:omega-3 PUFA ratio was positively associated with excessive adiposity and a worse metabolic profile, whereas the association between adiponectin and omega-3 PUFAs was linked with a better inflammatory profile and lower levels of proinflammatory tumor necrosis factor alpha (TNF-α). In a comparative study, two omega-3 fatty acids, EPA and DHA, were supplemented for a period of 10 weeks among 48 men and 106 women (Allaire et al., 2016). Compared

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to EPA, DHA was associated with a greater increase in adiponectin and was more effective in modulating different markers of inflammation. Overall, regular consumption of omega-3 fatty acids has exhibited an improvement in the concentrations of adiponectin in subjects with insulin resistance or type 2 diabetes (Mazaherioun et al., 2017; Farimani et al., 2018; Bahreini et al., 2018). It is worth mentioning that insulin resistance has a close link with the metabolic abnormalities of different organ systems such as nonalcoholic fatty liver disease (NAFLD), cardiovascular disorders, and polycystic ovary syndrome (Reccia et al., 2017; Tasic and Lovic, 2018; Moghetti, 2016). Furthermore, as mentioned previously, insulin resistance increases cancer risk (Orgel and Mittelman, 2013). Interestingly, studies have documented that supplementation of fish oil or omega-3 PUFA resulted in an increase in blood concentrations of adiponectin in patients with NAFLD (Qin et al., 2015; Spahis et al., 2018). Similarly, omega-3 fatty acid supplementation resulted in an enhancement in the plasma levels of adiponectin in patients with polycystic ovary syndrome (MejiaMontilla et al., 2018; Yang et al., 2018). In a two-month, double-blind, placebocontrolled clinical trial, omega-3 supplementation exhibited an increase in serum levels of adiponectin in individuals with at least one cardiovascular risk factor, for example, excess body weight, hypertension, dyslipidemia, diabetes, or smoking (Barbosa et al., 2017). The investigators of this study suggested that adiponectin is one of the mechanisms/factors by which omega-3 improves the cardio-metabolic profile in persons with cardiovascular risk. In an experimental animal model, DahlS.Z-Leprfa/Leprfa (DS/obese) rats were administered EPA from age 9 to 13 weeks (Ito et al., 2016). Of note, DS/obese rats are a model of metabolic syndrome and are derived from a cross between Dahl salt-sensitive rats (hypertension model) and Zucker rats (obesity model). Nevertheless, the treatment of DS/obese rats with EPA did not affect hypertension but reduced cardiac fibrosis and diastolic dysfunction. Moreover, EPA increased the circulating levels of adiponectin (Ito et al., 2016). On the other hand, a number of studies on different rat models showed that dietary supplementation with omega-3 fatty acids increased plasma adiponectin levels (Sekine et al., 2008; Duda et al., 2009; Hosoyamada and Yamada, 2017; Kobyliak et al., 2018). Like rats, various mouse models also displayed higher circulating levels of adiponectin with the intake of diets rich in omega-3 fatty acids (Flachs et al., 2006; Sundaram et al., 2016; Pærregaard et al., 2016). In case of both alcoholic hepatic steatosis and nonalcoholic steatohepatitis (NASH) in experimental animals, studies observed that omega-3 fatty acids upregulated blood concentrations of antiinflammatory adiponectin and prevented liver damage (Wang et al., 2016b; Konuma et al., 2015). As mentioned earlier, NAFLD is closely associated with obesity-related complications such as insulin resistance and metabolic syndrome, and the disease can progress from simple steatosis (fat accumulation) to more severe NASH (Brunt et al., 2015; Dietrich and Hellerbrand, 2014). Notably, NASH is characterized by typical histological features resembling alcoholic steatohepatitis, and both are considered important causes of liver cirrhosis and hepatocellular carcinoma (Tanaka et al., 2017).

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Like the above-mentioned epidemiological study (Allaire et al., 2016), an in vitro study revealed that DHA compared to EPA treatment led to a greater increase in adiponectin secretion in 3T3-L1 preadipocytes (Murali et al., 2014). In contrast, a study by Pinel et al. (2016) reported that in 3T3-L1 cells, DHA stimulated leptin expression whereas EPA induced adiponectin expression. In this connection, they suggested an improvement of the leptin/adiponectin balance, which may contribute to the protective effect of EPA. Nonetheless, another study on 3T3-L1 cells observed that adiponectin secretion was increased by treatment with both EPA and DHA (DeClercq et al., 2015). According to a report by Prostek et al. (2014), EPA and DHA increased the concentration of secreted adiponectin only in the case of young 3T3-L1 cells. Therefore, these investigators concluded that age is an important determinant that affects adipokine secretion by 3T3-L1 cells. In addition, their data supported a precise antiinflammatory action of DHA. Although long-chain omega-3 PUFAs have shown encouraging results in different experimental models of insulin resistance and related pathological conditions, their role is complicated in human studies. In the same way, omega-3 fatty acids are possibly effective in reducing cancer risk through a number of biological mechanisms. Perhaps the modulation of antiinflammatory adiponectin by omega-3 fatty acids is one of the important cancer-preventive mechanisms.

Conclusion Increasing trends of obesity and associated disorders are serious health issues throughout the world. Excess adipose tissue is linked with an increased risk for the development of cancer in different body sites. However, a growing amount of data suggests an important role of adipose tissue-released cytokines or adipokines in neoplastic processes. Lower circulating levels of adiponectin have been considered to be a risk factor for obesity-related diseases, including cancer. Therefore, understanding the precise function of this adipokine and its biological regulatory mechanisms could be helpful in cancer prevention and strategies in drug development.

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Lentils (Lens culinaris L.): A candidate chemopreventive and antitumor functional food Mo’ez Al-Islam E. Farisa, Mohammad G. Mohammadb, Sameh Solimanc a DE PARTMENT OF CLINICAL NUTRITION AND DIETETICS, COLLEGE OF HEALTH SCIENCES, UNI VERSI TY OF SHAR JAH, SHAR JAH, UNITED ARAB EMIRATES b DEPARTME NT OF MEDI CAL LABOR ATOR Y SCI ENCES, C OLLEGE OF HEALTH SC IENCES, UNIVERSITY O F SHARJAH, SHARJAH, UNI TE D AR AB EMI RATE S c DEPARTMENT OF MEDICINAL CHEMIST RY, COLLE GE OF PHARMACY, UNIVERSITY O F SHARJAH, SHAR JAH, UNIT ED ARAB E MIRAT ES

Introduction Pulses are healthy foods characterized by their unique content of a plethora of bioactive compounds. These include antioxidant polyphenols, phytosterols, dietary fibers, resistant starches, oligosaccharides, and bioactive peptides and proteins, all of which comprise a healthy amalgam that is associated with versatile health benefits for humans (Singh et al., 2017). A recent report highlighted the benefits of consuming legumes in cancer mortality prevention (Papandreou et al., 2019). Lentils (Lens culinaris L.) are part of the Leguminosae and constitute an important ingredient in many traditional recipes (Faris et al., 2013). Historically, lentils were among the early crops domesticated by humankind. The oldest lentils were dated to several archeological artifacts from as early as the Neolithic age (Zeder, 2008; Sonnante et al., 2009). Emerging attention has been directed toward lentils as a nutraceutical, functional food. This significance is ascribed to their good nutritional value as well as the presence of a plethora of phytoconstituents, including antioxidant nutrients and nonnutrient compounds, that constitute the health-improving properties of lentils. Nowadays, grain legumes have been looked at as nutraceutical functional food. Several researchers extensively reviewed the nutritional value and phytochemical content in these grains and their potential health-improving properties (Campos-Vega et al., 2010; Champ, 2002; Duranti, 2006; Roy et al., 2010; Scarafoni et al., 2007; Rochfort and Panozzo, 2007; Tharanathan and Mahadevamma, 2003). For lentil seeds, the disease-preventing and health-improving aspects have been supported by a growing amount of scientific evidence; they have been comprehensively reviewed by Faris and Attlee (Faris and Attlee, 2017; Faris et al., 2013). Epidemiological reports support that consumption of legume seeds, including lentils, is associated with reduced incidence of affluent chronic diseases Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00006-5 © 2020 Elsevier Inc. All rights reserved.

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such as diabetes, obesity, cancers, and cardiovascular disease (CVD) (Mills et al., 1989; Rizkalla et al., 2002; Kouris-Blazos and Belski, 2016; Curran, 2012). Throughout this chapter, the authors will try to highlight the significance of lentils as an anticancer and chemopreventive functional food that contributes to the functional properties for the healthy diet. This chapter was designed to provide a thorough review and update information regarding the anticarcinogenic and chemopreventive functional attributes for lentils exerted by their constituents of essential nutrients, bioactive substances, and antioxidants. This will be followed by epidemiological and experimental evidence along with proposed mechanisms for the anticancer chemopreventive properties of lentils.

Anticancer chemical constituents of lentils Plant phytochemicals are secondary metabolic products produced naturally by plants in order to perform unique functions, including protection and growth performance (Pagare et al., 2015). The natural production of plant phytochemicals and their existence in our foods make them applicable to humans because they are ecofriendly, safe, cheap, and simple to use. Plant phytochemicals were used by ancient people as their only source of medication. The use of plant chemicals was developed with the presence of chemistry and pharmacology techniques that help to assign special physicochemical characteristics and pharmacological activities of foods and food products, where many plant phytochemicals have been identified as potential anticancer candidates (Iqbal et al., 2017; Wang et al., 2012; Singh et al., 2016). Phytochemicals derived from lentils were revised in this chapter in relation to their proposed polarity and hence solubility. This was, first, to maximize the anticancer knowledge of the plant to the consumer, and second, to optimize the processing procedures of the plant. Therefore, this helps to gain the most beneficial way to use the plant. The polarity of plant phytochemicals is critical in determining the way of their extraction and hence the choice of the employed solvent system. For example, methanol is a solvent of choice for extracting phenolic compounds but not proteins (Iloki-Assanga et al., 2015). Thus, the selection of the proper solvent extraction method inevitably affects the ability to explore the plant composition from the health-improving bioactive phytochemicals, particularly the anticancer bioactive ones (Athmouni et al., 2015). Lentil anticancer phytochemicals were classified here according to their polarity/solubility into:

High polar phytochemicals Polyphenols Several reports indicated that lentils possessed the largest total phenolic content (TPC) compared to other leguminous seeds (Xu and Chang, 2007; Kalogeropoulos et al., 2010) and in comparison to the other 14 common legumes (Kalogeropoulos et al., 2010) with flavonoids (2109.6 μg/100 g), mainly catechins, representing the predominant polyphenolics in lentils.

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The TPC in lentils has been reported as 760 mg gallic acid equivalents (GAE) per 100 g, a total flavonoid content of 221 mg catechin equivalents per 100 g, and a condensed tannin content of 870 mg catechin equivalents per 100 g. A more recent study showed that, in comparison to 13 legumes, lentils showed the highest TPC values (1430 mg GAE/100 g). Further, lentils showed the second-highest procyanidin content (PAC); the second-highest value for the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity assay (19.3 μmole Trolox Equivalent (TE)/g); the fourth-highest value for oxygen radical absorbing capacity (95.2  3.11 μmole TE/g); the seventh-highest peroxyl radical scavenging capacities assay (60.5  1.46 μmole TE/g); and the fourth-highest cellular antioxidant activity (0.67 IC50 mg/mL). These results imply that lentils exhibit outstanding antioxidant capacities in vitro and greater TPC and PAC than many common legumes (Xu and Chang, 2012). These findings were proved later, where researchers found that lentils contained the highest total antioxidant activity (720.68 U/g), phenolic content (4760 mg/100 g), total reducing power, and DPPH scavenging activity (38.5%) when compared with 10 common leguminous seeds (Zhao et al., 2014). Lentil seeds contain high polyphenolic contents including condensed tannins, which may explain the dark color of the seed coats (Zou et al., 2011). Lentil polyphenols play an integral role in defeating degenerative diseases (Ganesan and Xu, 2017). Polyphenols have the ability to induce detoxification and suppress the activity of carcinogenic oxidizing agents (Faris et al., 2009), thus working as effective chemopreventive factors. Along with the chemopreventive effect of lentil polyphenols, lentil polyphenolic compounds showed an antitumor effect against thyroid and hepatic carcinoma in vitro (Zhang et al., 2015). Plausible mechanisms for the chemopreventive potential of phenolics include suppressing the formation of carcinogens, detoxification or deactivation of the carcinogen, inhibition of carcinogen uptake, enhancing DNA repair, and preventing carcinogen binding to DNA. Further, the antioxidant properties of lentil polyphenols include scavenging oxygen radicals and reactive electrophiles and halting the arachidonic fatty acid metabolism in the eicosanoids prostaglandin-E2 (PGE2) by cyclooxygenase-1 (COX-1) and -2 (COX-2) (Nichenametla et al., 2006; Spanou et al., 2007; Faris et al., 2009).

Proteins and bioactive peptides Lectins Lectins are soluble peptides present in lentil seeds. Lectins exhibit a therapeutic anticancer activity by binding to cancer cell membranes, triggering autophagy and apoptosis (De Mejı´a and Prisecaru, 2005). Further, lectins showed antiproliferative properties in colon cancer (Caccialupi et al., 2010), with the anticancer properties of lentil lectins being observed in various human in vitro and in vivo studies (De Mejı´a and Prisecaru, 2005). Lectins exert their anticancer activities through binding to cancer cell membranes/receptors and causing apoptosis, cytotoxicity, and autophagy, therefore inhibiting tumorigenesis (De Mejı´a and Prisecaru, 2005).

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Both polyphenols and lectins have the ability to bind to ribosomes and hence halt protein synthesis, thus suppressing cell proliferation and tumorigenesis. The underlying mechanisms of the anticancer potential of lectins and the phenolic compounds in lentils include that they can bind to ribosomes, which in turn hinders protein synthesis. This would aggravate changes in the cell cycle and trigger a nonapoptotic G1-phase accumulation, arrest the G2/M phase cell cycle, and apoptosis. Also, the inhibitory effect may work in downregulating telomerase activity and activating the caspase cascade in mitochondria, which in turn suppresses angiogenesis (De Mejı´a and Prisecaru, 2005; Scarafoni et al., 2007). The proposed mechanisms of the antitumor effect of lectins stem from their ability to induce plasma membrane changes, bind to ribosomes, and, accordingly, inhibit protein synthesis, which interferes with cell growth. Lectins also work in arresting the cell cycle through triggering the nonapoptotic accumulation of the G1 phase and arresting the G2/M phases (De Mejı´a and Prisecaru, 2005). Therefore, lentil polyphenolics and lectins confer promising antitumor effects against cancer cell agglutination and/or aggregation or tumorigenesis. Gastrointestinal cancers are among the targeted types of cancer for lectins, both in diagnosis and treatment (Estrada-Martı´nez et al., 2017). Among the proposed mechanisms of lentils and other leguminous peptides against gastrointestinal cancers is the inhibition of matrix metalloproteases, disruption of the mitochondrial membrane, prevention of DNA damage, interaction with membrane receptors, and induction of apoptosis (Luna-Vital and De Mejı´a, 2018). Further, other researchers (Sames et al., 2001; Wang et al., 2000) proved the repressor effect of lentil agglutinin against skin melanoma and hepatoma cell lines. It has been proposed that lectins could be used as a noninvasive screening tool for colorectal cancer (CRC) and for the early detection of cancer, as they showed an ability to bind to human colonocytes and thus anticipate the existence of premalignant and malignant colonic aberrations (Desilets et al., 1999). Additionally, lentil lectins are not toxic, so they provide safe use in medical diagnostics (Mitchell et al., 1998). Several reports investigated the effects of lentil lectins, polyphenols, and flavonoids on transformed cell lines. Lentil lectin and flavonoid supplementation have shown antiproliferative and anticancer activities to human colon adenocarcinoma HT29, human colon carcinoma Caco-2, colonic fibroblast CCD-18Co, and the nasopharyngeal carcinoma CNE1 and CNE2 cell lines (Caccialupi et al., 2010; Rodrıguez-Juan et al., 2000; Chan et al., 2015).

Defensin Defensin is an antimicrobial peptide detected in lentils (Finkina et al., 2008). Defensin showed potential anticancer activities (Guzma´n-Rodrı´guez et al., 2015). Extracted defensins showed the ability to deter ion channels and inhibit protein translation, thus aiding in halting tumorigenesis. Also, defensins showed antiproliferative potential against tumor cell lines (Finkina et al., 2008). The anticancer activities of plant antimicrobial peptides such as defensins suggest that they may be used as alternative therapies against cancer (Guzma´n-Rodrı´guez et al., 2015). Broad activities have also been determined, including

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antimicrobial, immune modulation, and demonstrated antitumor activity in several transformed cell lines (Salas et al., 2015).

Protease inhibitors Trypsin and protease inhibitors are proteins that possess the ability to inhibit cell proliferation in particular prostate and colon cancers (Guillamo´n et al., 2008). Trypsin or protease inhibitors were classically known as antinutritional factors, as they were reported to hamper protein and starch digestibility (Savelkoul et al., 1992). Nowadays, these protease inhibitors have been looked at as potent anticancer compounds, as they have the ability to suppress cancer cell proliferation, particularly for cancers of the prostate and colon. Among these protease inhibitors are Bowman-Birk inhibitors (BBIs), which have been examined in the field of cancer therapy. BBIs are present at greater amounts in pulse grains in comparison with other plants. Many beneficial functional and biochemical attributes have been proved for BBIs, including their efficacy against in vitro tumor cells (Losso, 2008; Scarafoni et al., 2007). Proteases play major roles in cancer metastasis; therefore, suppressing their activities by protease inhibitors contributes to halting carcinogenesis (Losso, 2008). Undoubtedly, BBIs can prevent and suppress cancer in various in vivo and in vitro experimental models (Kennedy, 1998). Scientific evidence suggests putative clinical applications for BBIs in skeletal muscle atrophy, radioprotection, autoimmune diseases, obesity, multiple sclerosis, and inflammation (Armstrong et al., 2000; Kennedy, 1998). The BBI mechanism of action can include suppression of reactive oxygen species development, triggering DNA repair through a p53-dependent mechanism, and antiproliferative activity by stimulating the expression of connexin 43 (Srikanth and Chen, 2016). However, soaking/cooking or heat processing of lentils and other BBI-containing pulses has been shown to hinder their activity significantly and markedly reduce the levels of these enzyme inhibitors (Shi et al., 2017). Further, BBIs derived from mature lentil seeds have been shown to halt cell proliferation of cancerous colonocytes in a dose-dependent manner by virtue of their ability to restrain serine proteases (Armstrong et al., 2000).

Phytosterols Phytosterols (plant sterols) are alcohol-soluble molecules present in the cell membranes of plants, including lentils (Kalogeropoulos et al., 2010). Phytosterols showed protection against common types of cancers including prostate, breast, and colon (Awad and Fink, 2000). Phytosterols have the ability to affect the cancerous cell membrane structure, membrane fluidity (Spector and Yorek, 1985), and membrane integrity (Awad et al., 2000). Furthermore, phytosterols can also enhance the human immune system (Bouic et al., 1996).

Saponins Lentils contain saponin glycosides and sapogenol A and B of the triterpene type (Srivastava and Vasishtha, 2012). Saponins are plant glycosides that are characterized

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by having a strong foam-forming property in aqueous solution. Further, saponins have different antitumorigenic effects based on their structures. One of the most known antitumorigenic mechanisms of saponin glycosides is attributed to its cholesterol-binding ability. Therefore, this can inhibit the growth of cholesterol-rich cancer cells and/or kill them. The polarity and hydrophobic properties of saponins are important determinants of their biological properties (Rao and Gurfinkel, 2000). Cooking lentils caused the degradation of lentil saponin with a loss of 15%–31% (Ruiz et al., 1996). Lentils are looked at as one of the superior sources of saponins, with an estimate of 34 mg of saponins per 100 g of lentils. Saponins in lentils are expressed as soya sapogenol B. In this regard, different saponins extracted from different plants have been reported as possible antitumor agents € u € c¸lu € -Ust € ndag˘ and Mazza, 2007). (Gu

Medium polar phytochemicals Flavonoids Lentils contain several flavonoid compounds, including flavonols, flavan-3-ols, flavanones, flavones, and anthocyanidins; these greatly contribute to the chemoprevention activity of lentils (Lee et al., 2017). Jin and colleagues ( Jin et al., 2012) characterized proanthocyanidins (polymeric and oligomeric flavonoids) in lentils and revealed that procyanidin and prodelphinidin-type flavan-3-ol subunits were the principal proanthocyanidins found in lentils ( Jin et al., 2012). The major anticancer flavonoids found in lentils include kaempferol, quercetin, and myricetin; are all protective agents against breast cancer (Adebamowo et al., 2005). Another is genistein, which is dimethyl sulfoxide-soluble isoflavone (Wu et al., 2010) isolated from lentil seeds that showed proapoptotic function against CRC (Iqbal et al., 2017). Genistein performs various functions, including inhibiting the topoisomerase II enzymes (Mizushina et al., 2013; Luo et al., 2014), upregulating the expression of proapoptotic proteins (p21 and Bax), and upregulating glutathione peroxidase (Ganai and Farooqi, 2015). Genistein is one of the natural phytochemicals that has been examined in epidemiological, preclinical, and early clinical studies for its role in cancer treatment and prevention (Wang et al., 2012). Further, flavonoids and lentil lectins were indicated as suitable markers of prognosis in patients with thyroid cancers (Kanai et al., 2009).

Less polar phytochemicals Squalene Triterpenoid squalene is a lentil component that showed chemopreventive potential against CRC (Rao et al., 1998). It has been demonstrated that squalene diminishes the activity of the β-Hydroxy β-methylglutaryl-CoA reductase enzyme and hence renders the production of farnesyl diphosphate inactive. Farnesyl production is required for protein prenylation. Inhibition of prenylation of ubiquinone proteins inactivates the signal transduction in the proliferation of oncogenes and guanosine triphosphate-binding proteins (Warleta et al., 2010; Smith, 2000). Furthermore, squalene has been reported to be

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used as a lipid carrier adjuvant in cancer therapeutics. Linking squalene with anticancer drugs such as gemcitabine or doxorubicin in the form of nanoparticles caused a reduction in drug toxicity while increasing anticancer activity (Peramo et al., 2018).

Insoluble lentils products Fibers Insoluble fibers in lentils represent the vast majority of fibers (Bednar et al., 2001). Insoluble fibers showed potential anticancer and antitumor activities (Demirbas, 2005). Epidemiological studies suggest that the consumption of fiber-rich foods, such as lentils, is associated with a reduced risk of breast cancer (Chaje`s and Romieu, 2014). Further, a similar effect was found against colon cancer, with the mechanism of the chemopreventive effect of insoluble fibers against colon cancer attributed to the ability of these fibers to enhance stool bulkiness and hence dilute fecal carcinogens. Thus, fibers shorten the transit time of stool passage through the intestinal tract and hence reduce the contact of carcinogens with the colon mucosa (Weisburger et al., 1993).

Phytic acid (hexaphosphorylated inositol, IP6) Phytic acid (IP6) is a major component of lentil fiber. It is the phosphorous-rich compound in pulses (Moon et al., 2006; Morris and Hill, 1996). Phytic acids are present in lentils in considerably high amounts (620 mg per 100 g of lentils) (Ayet et al., 1997). Dietary phytates have been shown to halt colorectal carcinogenesis (Marks et al., 2006). Several mechanisms have been proposed to explain the antineoplastic activities of IP6. Phytic acid can hinder the proliferation of CRC (Barahuie et al., 2017). On the other hand, IP6 can be engulfed by cancer cells, causing changes in their biochemical signal transduction pathways; therefore, this can alter the cell cycle and/or activation of the apoptosis mech€ terova´ et al., 2018). Further, the alteration of signal transduction pathways anism (Schro ends up arresting the cell cycle, making suppression of cell proliferation as one of the proposed mechanisms of the anticancer effect of IP6. IP6 has also been involved in the inhibition of tumor metastasis and angiogenesis, the inauguration of apoptosis, the enhancement of immunity, and the induction of differentiation of malignant cells. Several reports indicated the ability of IP6 to work as an antioxidant and antiinflammatory compound, and to reduce the expression of xenobiotic metabolizing enzymes. This triggers overexpression of detoxifying enzymes and tumor suppressor genes, and finally the suppression of proto-oncogenes (Fox and Eberl, 2002; Verghese et al., 2006; Vucenik and Shamsuddin, 2006). Early reports on cancer patients uncovered that IP6 and inositol have the ability to boost the quality of life by abbreviating the side effects of chemotherapeutics, to augment the antitumor effect of the common medical chemotherapies, and to restrain the cancer metastasis (Vucenik and Shamsuddin, 2006). The aforementioned summarized data showed that lentil seeds contain several anticancer components with variable solubility, including polar (polyphenols and proteins), medium polar (flavonoids), less polar (triterpenoids), and insoluble products (Fig. 6.1).

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OH OH O

HO

OH OH OH HO

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P

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Sapogenol

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Genistein

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Phytosterol FIG. 6.1 Anticancer components of lentils.

Epidemiological evidence on the chemopreventive potential of lentils Legumes are an integral constituent of the traditional cuisine of many long-lived food cultures such as that in Japan, whose residents routinely consume soybean-based foods, and people from the Mediterranean region, where legumes such as lentils represent renowned dietary components (Kouris-Blazos and Belski, 2016). In the last few decades, numerous

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observational studies have shown that consuming legumes is associated with a lowered incidence of many types of cancers, especially CRC (Sa´nchez-Chino et al., 2015), prostate, colon, thyroid, liver, and breast (Caccialupi et al., 2010; Adebamowo et al., 2005; Perabo et al., 2008), with more emphasis on lentil or bean intakes lowering the risk of breast cancer (Adebamowo et al., 2005). As part of the observational studies, case-control studies support that legume consumption can pointedly decrease the risk of CRC. Consumption of lentil seeds has been linked to an incidence reduction in various cancers, and the anticancer activity is attributed to lentil bioactive phytochemicals (Ganesan and Xu, 2017). In a prospective study that included more than 90,600 women, lentils were the sole food that exhibited an inverse protective association with breast cancer risk among an ample number of flavonoid-rich foods (Adebamowo et al., 2005). This was attributed, in part, to the low glycemic load (GL) and low glycemic index (GI) properties for lentils and other dried beans. It has been proposed that frequent consumption of high GL and high GI foods, such as those typically consumed in the Western diet, is associated with hyperinsulinemia and hyperglycemia associated with metabolic disturbances that predispose the increased incidence of CRC (Bruce et al., 2000). In Uruguay, a case-control study of 11 cancers included about 3540 cases, and 2032 controls revealed that those people with the highest versus the lowest tertile of lentil intake were associated with a highly compelling decreased risk of cancers of the pharynx and oral cavity, esophagus, larynx, upper aerodigestive tract, colorectum, and kidney, and all cancers combined (Aune et al., 2009). Further, a systematic review and meta-analysis for 14 cohort studies included 1,903,459 participants, and 12,261 cases revealed that higher legume consumption was associated with a reduced risk of CRC while the subgroup analyses suggested that higher legume consumption was inversely associated with CRC risk in Asian populations (Zhu et al., 2015). Later, another meta-analysis confirmed the same finding using both human and animal studies. Eleven prospective cohorts and 12 casecontrol studies were meta-analyzed. The findings showed that higher legume consumption, including lentils, confers a protective effect against CRC (Perera et al., 2016). Further, 14 animal studies were meta-analyzed and showed, except for one study, an ability to suppress colorectal tumorigenesis (Perera et al., 2016). Most recently, the chemopreventive effect of lentils was further confirmed by GarciaLarsen and colleagues, who systematically reviewed and meta-analyzed 28 case-control and cohort studies for the relationship between dietary patterns and the risk of CRC. Their results showed that a healthy balanced dietary pattern that includes legumes was inversely associated with CRC in comparison to the Western dietary pattern, which lacks legumes (Garcia-Larsen et al., 2019). Another recently published long-term observational prospective cohort study with a 6.0 year median follow-up revealed that the hazard ratios of total legume and lentil (average of 6.7 g/day) consumption was associated with a 49% and a 37% lower risk of cancer mortality, respectively (Papandreou et al., 2019). Relevant findings were found consistent with a meta-analysis that surveyed approximately 280,000 participants and 10,000 prostate cancer patients, which found that a daily intake of 20 g of legumes would reduce the incidence of prostate cancer by 3.7% (Li and Mao, 2017).

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Experimental evidence In vivo studies Preclinical research has also uncovered that consuming leguminous seeds by experimental animals attenuated colon carcinogenesis in azoxymethane (AOM)-induced colon cancer (Bobe et al., 2008), and reduced both the number and incidence of colon tumors by 50% (Bennink, 2002). Noticeably, fewer preclinical in vivo studies in comparison with in vitro studies have been conducted on the chemopreventive potential for lentils and in comparison with other types of legumes. The chemopreventive activity of lentil seeds against experimental colorectal carcinogenesis was first investigated by Faris and partners (Faris et al., 2009; Shomaf et al., 2011). Using AOM to chemically initiate colon carcinogenesis in Fischer 344 rats, mimicking the initiation/promotion and progression model of sporadic human CRC, the chemopreventive effect of lentil seeds was examined in rodents fed different lentil diets: cooked whole, raw whole, cooked split, and raw split lentils before and after the carcinogen AOM injection. Feeding lentil diets substantially decreased the number of neoplasms and dysplastic lesions in the colons of rats fed on lentil diets when compared with control (Shomaf et al., 2011). This also reduced the number of aberrant crypt foci (ACF) and preneoplastic lesions that predispose colon carcinogenesis. ACF were used as an indicative marker for chemoprevention trials, where ACF count, crypt size, and multiplicity were substantially reduced in rat groups fed different lentil diets in comparison with the control diet (Faris et al., 2009). Raw whole lentils showed a small reduction of 26.8% in rats, whereas cooked whole lentils showed a massive reduction (about 78%) in large ACF. Because large ACF predict more accurately the preneoplastic activity for chemopreventive material, this suggested that lentils may work in retarding the progression of the early precancerous lesions, thus providing a suppression model of early initiation of carcinogenesis. Whole cooked lentils exhibited the largest reduction (about 65%) in AC from multicrypt foci. This inhibitory effect of lentils against ACF was further confirmed by Busambwa and partners, who found that nonsprouted and sprouted, and lentils reduced ACF initiated by AOM, with a concomitant substantial expansion in glutathione-S-transferases (GSTs), glutathione, and catalase enzymes activities (Busambwa et al., 2014). Faris and partners (Faris et al., 2009) also found that the chemoprevention ability of lentils in F344 rats was accompanied with increased activity of the xenobiotic detoxifying hepatic enzyme GSTs in all lentil-fed groups when compared with the control diet (Fig. 6.2). Like those found in other legumes, lentil antioxidant polyphenolics are among the monofunctional triggering factors that induce the activity of detoxifying enzymes alone (Pool-Zobel et al., 2005). The finding that levels of hepatic detoxifying enzymes (GST) were considerably greater in rats fed chemopreventive lentils than in rats fed a control diet implies an increased capacity to defend against oxidative stress triggered by exposure to chemopreventive agents (Pool-Zobel et al., 2005). Further, the induced hepatic GST of rats fed on split lentils could be partly ascribed to the presence of considerable amounts

Chapter 6 • Lentils: Anticancer functional food

GST activity(mcmol\mg\min)

80

109

*

70

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*

*

*

50 40 30 20 10 0

C

C+5%RWL

C+5%CWL

C+5%RSL

C+5%CSL

C+5%RSB

Diet FIG. 6.2 Increased hepatic glutathione-S-transferase (GST) activity by the exposure to lentils and soybean chemopreventive effect. C, control; CSL, cooked split lentils; CWL, cooked whole lentils; GST, glutathione-Stransferases; RSB, raw soybean; RSL, raw split lentils; RWL, raw whole lentils. This figure is derived from an Elsevier journal (Nutrition Research): Faris, M. E. A.-I. E., Takruri, H. R., Shomaf, M. S., Bustanji, Y. K., 2009. Chemopreventive effect of raw and cooked lentils (Lens culinaris L) and soybeans (Glycine max) against azoxymethane-induced aberrant crypt foci. Nutr. Res. 29, 355–362.

of phytic acid in the cotyledons. It was found that levels of GST were concomitantly expanded with increasing polyphenolics, phytic acid, and inositol content in the tested diets, once compared with control. Phytic acid has been reported to suppress colon carcinogenesis via the chelation of iron and the suppression of iron-related initiation and promotion of carcinogene. Also, it may have a therapeutic application in suppressing tumorigenesis by virtue of its property to augment the activity of natural killer cells associated with repressed carcinogenesis (Khatiwada et al., 2006). Further, lentils showed a higher chemopreventive potential when compared with other leguminous grains such as yellow and green peas (Busambwa et al., 2014). It has been reported that reducing the ACF and number may be ascribed to the effect of phytochemical compounds working as blocking agents or preventing carcinogenesis initiation (Chen and Kong, 2005). These blocking agents impede colon carcinogenesis by diverse mechanisms, including the inhibition of cytochrome P450-mediated activation of carcinogens, the enhancement of detoxification of carcinogens, halting antioxidant activity and scavenging free radicals, and finally trapping the carcinogen and halting its interaction with DNA (Chen and Kong, 2005). For the large multicrypt ACF, the decreased number reflects the capacity of the tested chemopreventive agent to work as a suppressing agent or to hamper cancer promotion. This devaluation in the large ACF with high multiplicity has been associated with lowered levels of COX-2 and inducible nitric oxide synthase (Takahashi et al., 2000). Other studies associated this chemopreventive effect with the production of PGE2, the upregulation of apoptosis, the suppression of proliferation, and cyclin D1 protein expression (Sengupta et al., 2004; Tanaka et al., 2000b, a). Other biomarkers such as COX-2 mRNA in the colonic mucosa, urinary levels of oxidative

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DNA damage, and expression of COX genes have also been used in experimental chemoprevention trials (Lala et al., 2006). Further research is warranted to elucidate the molecular, epigenetic, and genetic pathways underlying the chemopreventive potential of lentil seeds against colon carcinogenesis. The ability of lentils to suppress colon carcinogenesis could be partly explained by virtue of their presumptive antioxidant potential and by the existence of cotyledonous bioactive agents rather than the antioxidant phytochemicals present in the seed coat. Also, the presence of considerable amounts of the trace mineral selenium in lentils may also contribute to the chemopreventive activity of lentils, as this microelement is involved in the enhancement of the immune system and the induction of apoptosis (Arthur et al., 2003). As a result of the accumulating knowledge regarding the chemopreventive activity of lentils, different attempts have been initiated to familiarize the consumption of the health-improving, nutrient-dense lentils for different community groups. Food manufacturers and technologists have tried to develop healthy snack bars using micronized flakes of lentils (Ryland et al., 2010).

In vitro studies Several studies have identified the antitumor activity of lentils by testing the antitumor potential on in vitro cell lines, aiming to examine cancer development pathways at different points of tumor development (Rao et al., 2018). As a consequence of the outstanding high antioxidant potential and unique bioactive content of lentils (Xu and Chang, 2012), in vitro studies showed that lentils exhibited dose-dependent suppressor effects against cell proliferation of different cancer cell lines (hepatocellular carcinoma cell HepG2, ovary adenocarcinoma cells SK-OV-3, colorectal adenocarcinoma cell Caco-2, tongue squamous carcinoma cell CAL27, colorectal adenocarcinoma cell SW 480, breast adenocarcinoma cells MCF-7, gastric adenocarcinoma cell AGS, and leukemia cells HL-60) while also showing the forceful repressor effect against prostate carcinoma cell Du145 among the tested 13 leguminous seeds (Xu and Chang, 2012). The anticancer potential of lentil crude proteins was further examined against the tumor cell lines Caco-2, HeLa, HEP-2, and HepG-2 cells using an MTT assay. The results showed that lentil crude proteins possess cytotoxic activity only against HepG-2 and HeLa cancerous cells (Badria, 2014). In our laboratory, we investigated the killing activity of lentil extracts from whole and decorticated lentil seeds, and their seed coats against the MCF7 breast cell line. Using an MTT assay, the antitumor killing activity was compared with the killing activity against a nontransformed human fibroblast cell line. Although the killing activity against MCF7 cells was observed in all three extract treatments, extracts from seed coats showed a drastically reduced 50% antitumor killing potential at 1 μg/ml dilution. The same treatments on the nontransformed fibroblast cell line showed minimum killing activity (Fig. 6.3). The obtained results indicated that polar components extracted from seed coats were more effective as anticancer agents while those polar components extracted from

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FIG. 6.3 Percentage of cell viability of MCF-7 cells at different dilutions of lentil fractions (A) whole lentil seed; (B) decorticated seeds or flesh; and (C) lentil seed coat extracts compared to the fibroblast cell line as a nonmalignant control (Faris et al., unpublished data).

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cotyledons were not. On the other hand, whole seed extracts did not show different activities when tested on either cancer or normal cells, indicating that polar components from cotyledons may normalize the anticancer effects of polar components from the seed coat. According to the “Like-Dissolves-Like” role, methanol can extract some polyphenols and flavonoids, but not proteins. This antitumor effect of lentils against the human breast cancer MCF-7 cell line is an echo for the finding of Xu and Chang on the same cell line (Xu and Chang, 2012). The significant increase in killing activity of the seed coat extract reported in our results and Xu and Chang’s results could be ascribed to the immense concentrations of phenolic phytochemicals found in the seed coat, which provide the increased antioxidant capacity in these coats (Xu et al., 2007). The antioxidant power of lentil seed coats was further confirmed by other researchers, who reported that the total antioxidant activity and phenolic content were reduced by about 80% in lentils upon decortication (Han and Baik, 2008). These findings could be further elucidated by the fact that seed coats of lentils were reported to be rich with procyanidins dimers and catechins, with minor quantities for myricetin, apigenin, quercetin, and luteolin glycosides. Contrarily, the cotyledons mainly include hydroxycinnamic acids and hydroxybenzoic (Duenas et al., 2006). More evidence for the condensed content with polyphenols in lentil seed coats is the well-established fact that the darkness of the lentil seeds coats is a reflection of their phenolic content. It was found that the darker the color of lentils, the higher their phenolic content and antioxidant activities (Xu et al., 2007; Xu and Chang, 2010). Further, other studies reported that aqueous ethanolic extract (80%) of lentil hulls had high antiinflammatory activities, preferentially inhibiting 15-LOX with moderate COX-1 and COX-2 inhibitory effects on the COX pathway (Boudjou et al., 2013). This finding agrees with that reported by Zia-Ul-Haq and partners, who found that crude methanolic extracts of lentils examined for antiinflammatory activity by a COX-2-producing PGE2 inhibitory assay had 74.5% inhibition at a 20-mg/mL extract concentration (Zia-Ul-Haq et al., 2013). The latter study could explain the relationship between the reduced incidence of inflammatory bowel diseases, which imposes a risk factor for CRC, and the frequent consumption of legumes that possess antiinflammatory activity (Zhu et al., 2018). Gelatinase B, also known as matrix metalloproteinase 9 (MMP9), is an MMP that is closely associated with metastatic and aggressive breast cancer (Mehner et al., 2014). Among eight selected legume species, lentil protein fractions were tested against MMP9 activity in colon carcinoma cells (HT-29 cell line). Lentil protein fractions (globulin and albumin) exhibited a moderate effect against MMP9 gelatinolytic activity in comparison with the other leguminous protein fractions, a matter that was ascribed to the relatively lower content of BBI in lentil proteins in comparison with the other tested leguminous proteins (Lima et al., 2016), with lupine and lentil proteins showing the most powerful inhibition against HT-29 cell migration and proliferation. These findings suggest that legume proteins, including lentils, could be looked at as novel MMP9 metalloproteinase inhibitors with possible pharmacological interest against colon cancers, and

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emphasize the significance of including lentils and other leguminous species in the daily diet as anticancer food (Rao et al., 2018). Further, protease inhibitor peptides from lentils and other leguminous seeds (chickpea, kidney bean, mung bean, and peas) demonstrated antiproliferative potential and exhibited effective inhibition toward the epithelial human breast cancer cell line MDA-MB-231 (Magee et al., 2012). Nonsprouted and sprouted and lentil extracts exhibited clear cytotoxic and apoptotic effects, where lentil extracts persuade dose-dependent cytotoxicity in Caco-2 cells with a 20%–80% inflation in cytotoxicity percentage (measured as lactate dehydrogenase release) observed in cells incubated with extracts compared to untreated cells. Nonsprouted lentil extracts showed a lower total fragmented DNA percentage in cells treated with sprouted extracts. More than 40% of total DNA fragmentation was reported in cells treated with sprouted lentils, with increased activity of caspase-3. These reported apoptose and cytotoxic activities induced by lentil extracts make lentils, by virtue of their bioactive constituents, a candidate to be used as chemopreventive antitumor natural agents against different cancers (Busambwa et al., 2016). Bioactive phytochemicals of lentils and other dried leguminous seeds have been found to be improved in lentil seeds upon germination, where their contents of polyphenols, vitamins, and γ-aminobutyric acid increased, therefore increasing the total antioxidant activity in the germinated seeds (Gan et al., 2017; Aguilera et al., 2014).

Remarks and conclusions The anticarcinogenic potential of lentils is ascribed to the treasure of antioxidant bioactive phytochemicals, including flavonoids (anthocyanidins, tannins, including condensed tannins or proanthocyanidins, flavones, flavonols, flavanones, and flavan-3-old) that immensely instigate the chemopreventive potential. However, this chemopreventive potential is not restricted to polyphenolic-rich lentil or split seeds (Ganesan and Xu, 2017), but rather to saponins as well as bioactive peptides and proteins. The anticancer impacts of separate bioactive phytochemicals of lentils had been extensively elaborated. However, the anticancer activity of lentils as a conventional food had not been sufficiently elucidated. Although the epidemiologic evidence supports the antitumor chemopreventive potential of lentils against several cancers, the anticancer mechanisms of lentils are still unknown. Thus, further research is recommended to investigate the exact mechanistic pathways involved in this chemopreventive antitumor potential of lentil seeds. People should have adequate and full information and education about their daily nutrition to maximize its benefits while avoiding adverse effects. Thus, it is suggested that phytochemical rescreening of lentil seeds should be conducted to provide the full spectrum on the phytochemical composition of each seed part in relation to pharmacological activities and comparative processing procedures. Moreover, processing lentil seeds in the form of supplementary food that can occupy balanced components may provide powerful health benefits to the human body, particularly including chemoprevention against cancer.

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Evidence for anticancer properties of honey with emphasis on mechanistic overview Avinash Kundadka Kudvaa, Suresh Raob, Pratima Raob, Michael L.J. Paisc, Mohammed Adnanc, Karkala Sreedhara Ranganath Paid, Manjeshwar Shrinath Baligab b

a DEPARTME NT OF BIOC HE MISTRY, MANGALORE UNIVERSITY, MANGALOR E, INDIA MANGALORE INSTITUTE OF ONCOLOGY, MANGALOR E, INDIA c F AT H ER M U L L E R ME DI CA L COLLEGE, MANGALORE, INDIA d DEPARTMENT OF PHARMACOLOGY , MANIPAL COLLEGE OF PHARMACEUT ICAL SCIENCES, MANIPAL ACADEMY OF HIGHER EDUCATION, MANIPAL, INDIA

Introduction Cancer is a global epidemic. It is the second most deadly condition, causing an estimated 9 million deaths in 2018 alone. Of that, more that 70% of the deaths occur in low- and middle-income countries (McGuire, 2016). Not only are the causes of cancer very diverse, but also the economic burden of cancer is huge, with an estimated annual cost of $1.16 trillion worldwide (McGuire, 2016). The increasing population, exposure to infections, and the age-specific rate of cancer have been the major causes of concern in developing countries. The cancers associated with diet and lifestyle have been considered major concerns among developed countries. In order to understand the modalities to treat cancer, we need to recognize the factors that can cause cancer. The occurrence of cancer is a multistep process that encompasses many causes. The causes of cancer can be classified into: 1. Age and lowered immunity status may be due to chronic illness, old age, or metabolic disorders such as diabetes. 2. Chronic infections, for example, human papilloma virus (cervical cancer), hepatitis viruses (hepatocellular carcinoma), and trematode worms (bladder cancer). 3. Chronic inflammation and ulcers, for example, colorectal cancers in colitis patients (Crohn’s and ulcerative disease) and skin ulcers developing into squamous cell carcinomas. 4. Genetic inheritance.

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5. Free radicals or oxidative stress generated due to toxins from smoking, alcohol, chronic inflammation, etc. 6. Unknown etiology. Overall, the main cause of cancer is genetic damage within cells that is inherited or acquired during one’s lifetime. The treatment regimen includes surgery, chemotherapy, and radiation therapy. However, these modalities may have serious side effects. Hence, newer treatment methods that can specifically target carcinogenesis are the mainstream research focus in the current world. Household natural products such as honey has been reported to have anticancer effects (Othman, 2012). Honey has been a condiment known to mankind for centuries due to its medicinal and health benefits. Honey contains a variety of sugars and phytochemicals with high flavonoid and phenolic compounds (Tables 7.1–7.5) that confer potential antioxidant activity (Krystyna Pyrzynska, 2009; Lihu Yao et al., 2003; Iurlina et al., 2009).

Chemistry of honey Honey contains >200 different natural compounds (Ahmed et al., 2018; Eteraf-Oskouei and Najafi, 2013). Depending on the source, honey can be broadly classified as monofloral or polyfloral (multifloral). The smell, flavor, and color of honey mainly depend on the floral source that bees have foraged (Ahmad et al., 2017). A nutritive composition of honey is Table 7.1 Principal phenolic compounds present in honey (Santos-Buelga and Gonza´lez-Parama´s, 2017). Phenolic acids Benzoic acids 4-hydroxybenzoic Protocatechuic Gallic Vanillic Syringic Flavonoids Flavanones Hesperetin Pinocembrin Naringenin Galangin Kaempferol Quercetin Isorhamnetin Myricetin

Cinnamic acids

Other acids

Cinnamic p-Coumaric Caffeic Ferulic

Phenylacetic Mandelic Homogentisic

Flavones

Dihydroflavonols

Chrysin Apigenin Luteolin Tricetin

Pinobanksin

Chapter 7 • Evidence for anticancer properties of honey

Table 7.2 Typical nutritive composition of honey (Bogdanov et al., 2008; Eteraf-Oskouei and Najafi, 2013). Components

Value per 100 g

Carbohydrates Sugars Dietary fiber Fat Protein Vitamins Riboflavin (B2) Niacin (B3) Panthothenic acid (B5) Vitamin B6 Folate (B9) Ascorbic acid Minerals Calcium Iron Magnesium Phosphorus Potassium Sodium Zinc Copper Manganese Selenium Fluoride Water Ash

82.4 g 82.12 g 0.2 g 0g 0.3 g 0.038 mg 0.121 mg 0.068 mg 0.024 mg 2 μg 0.5 mg 6 mg 0.42 mg 2 mg 4 mg 52 mg 4 mg 0.22 mg 0.036 mg 0.080 mg 0.8 μg 7 μg 17.10 g 0.20 g

Table 7.3 Main sugars present in honey (Santos-Buelga and Gonza´lez-Parama´s, 2017). Monosaccharides Glucose Fructose Disaccharides Sucrose Maltose Kojibiose Isomaltose Turanose Maltulose Palatinose

Galactose (occasional)

Nigerose Leucrose Isomaltulose Laminaribiose Leucrose Melibiose Trehalose Continued

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Table 7.3 Main sugars present in honey (Santos-Buelga and Gonza´lez-Parama´s, 2017)—cont’d Trisaccharides Erlose Theanderose Panose Maltotriose Isomaltotriose Isopanose Melezitose Higher oligosaccharides Isomaltotetraose Isomaltopentaose

Table 7.4

Raffinose Centose 1-Kestose Laminaritriose Planteose α-30 -Glucosyl-somaltose

Maltotetraose Nystose

Chemical composition of honey (Solayman et al., 2016).

Components

Average percentage

Glucose Fructose Sucrose Other sugars Minerals Protein Total acid (gluconic acid) Vitamins, enzymes, aromas Phenolic compounds

28.15 39.44 3.19 8.5 0.36 1.13 0.5 8000 years, beginning from the Stone Age era that continued across ancient civilizations all over the world (Ahmed et al., 2018; Bansal et al., 2005; Eteraf-Oskouei and Najafi, 2013). Honey is mentioned in the literature of Aristotle, Hippocrates, and Dioscorides as well as the Ayurveda, Greek, Roman, and Islam pharmacopeias, signifying its therapeutic use (Ahmed et al., 2018; Eteraf-Oskouei and Najafi, 2013). The scientific studies that were done according to the principles of modern medicine have now shown that honey possesses a plethora of health benefits. It has been determined to have various pharmacological effects such as antiinflammatory (Cooper et al., 2001), antimicrobial (Sherlock et al., 2010), antioxidant (Al-Mamarya et al., 2002), and antitumor properties (Swellam et al., 2003; Tomasin and Gomes-Marcondes, 2011). More importantly, honey has been shown to potentiate the antitumor activity of 5-fluorouracil, a chemotherapeutic agent (Gribel and Pashinskii, 1990). Few studies attribute polyphenols as the major factor for the anticancer properties of honey (Abubakar et al., 2012; Mandal, 2009; Tonks et al., 2007). At present, in vivo studies suggest that honey possesses anticancer properties (Table 7.6). With an increasing number of people seeking natural therapies, it is necessary to understand their mechanistic action. Hence, this section presents a synopsis of findings on various cellular pathways that enable honey to confer its therapeutic action.

Honey stimulates the immune system Regular intake of honey has been shown to improve antibody production due to immune responses (Fukuda et al., 2011). It has been shown to induce antibody production during immune responses (thymus-dependent and independent antigens) in mice when exposed to sheep red blood cells and E. coli (Al-Waili and Haq, 2004). Honey varieties such as Manuka, pasture, and jelly bush have been found to significantly induce inflammatory

Table 7.6

In vivo studies on the anticancer properties of honey.

Honey type

Type of cancer

Observations

Reference

1

Tualang honey

Breast cancer

Ahmed and Othman (2017)

2

Malaysian Tualang honey (TH) and Australian/New Zealand Manuka honey (MH)

Breast cancer

3

Tualang honey

Breast cancer

4

Wildflower honey

Walker 256 breast cancer cell implants

5

Jungle honey

Lewis lung carcinoma/2 (LL/2) cell implants

6

Manuka honey

Melanoma

7

Pure unfractionated honey from Manitoba (Tokyo, Japan)

Bladder cancer

8

Kelulut honey

Azoxymethaneinduced colon cancer

9

Pure unfractionated bee honey fed on Egyptian clover flowers

Methylnitrosourea (MNU)-induced carcinogenesis

Oral feeding of honey alleviates carcinogenesis through modulation of hematologic and apoptotic activities by lowering antiapoptotic protein (E2, ESR1 and Bcl-xL) expression and increasing proapoptotic proteins (Apaf-1 and Caspase-9) in experimental N-methyl-Nnitrosourea (MNU)-induced SpragueDawley (SD) rats Oral administration of honey in SD rats with breast cancer (induced by carcinogen: 1-methyl-1-nitrosourea) unregulated the proapoptotic proteins such as Caspase-9 and p53 and reduced the antiapoptotic proteins such as Bcl-xL and ESR1 Oral administration of honey to rats induced with breast cancer using 7,12dimethylbenz(α)anthracene (DMBA) showed reduced tumor size and lowered growth factors such as vascular endothelial growth factor (VEGF). Also, an increase in apoptotic index was observed Aloe vera and honey increased oxidative stress in cancer cells, but reduced host wasting and cachexia. The exact mechanism was unknown Intraperitoneal injection of honey in female C57BL/6 mice implanted with Lewis lung carcinoma/2 (LL/2) cells showed increased neutrophil population that may have mediated ROS-induced antitumor activity Cotreatment of manuka honey along with paclitaxel improved survival due to improved tumor apoptosis and reduced chemotherapy-induced toxicity MBT-2 bladder cancer-implanted C3H/He mice, when treated with honey, showed reduced tumor growth likely due to caffeic acid ester and flavonoid glycones and their inhibitory effects on lipoxygenases, tyrosine protein kinase, and cyclooxygenase Oral administration of honey in SD rats showed no toxicity while a significant reduction in aberrant crypt foci (ACF) and crypt multiplicity was observed Bee honey and Nigella sativa (NS) extract when given orally to SD rats reduced MNUinduced oxidative stress and also abolished malondialdehyde and nitric oxide levels

Ahmed et al. (2017)

Kadir et al. (2013)

Tomasin et al. (2015)

Fukuda et al. (2011)

FernandezCabezudo et al. (2013) Swellam et al. (2003)

Saiful Yazan et al. (2016)

Mabrouk et al. (2002)

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cytokines such as TNF-a, IL-1b, and IL-6 in M6 cells and human monocytes when compared to untreated cells (Tonks et al., 2003). Patients with weak immune systems have been considered at risk for cancer development. Aging being one such instance where the immune system diminishes accompanied by prolonged exposure to carcinogens can potentiate the incidence of cancer (Franceschi and La Vecchia, 2001). Thus, the key to cancer prevention is by improving the immune system and the use of honey seems to have such potential.

Honey as antioxidants Aging and many chronic and degenerative diseases are predisposed to oxidative stress (Halliwell and Gutteridge, 1989). Antioxidants are agents that neutralize the effects caused by oxidants such as superoxides (O2 ∗ ), lipid peroxides, hydroxyl radicals (*OH), nitric oxide (NO*), etc. Cells have natural systems in place that defend against damage, including tocopherol, catalase, superoxide dismutase, peroxidase, ascorbic acid, and polyphenols (Nagai et al., 2001). Honey of various floral origins and geographical areas has been shown to exhibit antioxidant properties (Erejuwa et al., 2012). The phenolic acids and flavonoids are mainly attributed to such activity. Apart from these, carotenes, organic acids, and Maillard reaction products have also been known to contribute to antioxidant effects (Aljadi and Kamaruddin, 2004; Nagai et al., 2001). Though the exact mechanism of the antioxidant mechanism is still unknown, researchers have shown that honey (1.2 g/kg) elevated the levels and activities of beta-carotene, vitamin C, glutathione reductase, and uric acid in healthy human subjects (Al-Waili, 2003a). Thus, the proposed mechanisms include free radical scavenging, flavonoid substrate action for hydroxyl groups, metal ion chelation, and superoxide radical actions (Al-Mamarya et al., 2002; van Acker et al., 1996). But there are still gaps in our understanding and its extrapolation to clinical use.

Honey as antiinflammatory agents Inflammation is a biological process of vascular tissues in response to harmful stimuli. It is a defense mechanism built to eradicate the pathogens or the stimuli that are the cause of injury. Inflammation is broadly classified into two classes: acute and chronic inflammation. Acute inflammation is the early response to stimuli, which leads to redness, pain, and loss of function (Vandamme et al., 2013). If not treated early, a prolonged stimulus can lead to chronic inflammation. Chronic inflammation has been attributed to several conditions such as cancer, kidney disease, and liver disease (Chant, 1999; Lee, 2004; Moneim and Ghafeer, 2007). Numerous proinflammatory factors such as cytokines, enzyme-like cyclooxygenases (COX), lipoxygenases (LOX), and mitogens are involved in this mechanism. The antiinflammatory action of honey is well established in cell cultures ( Jaganathan and Mandal, 2009), animal models, and human clinical trials (Al-Waili and Boni, 2003; Subrahmanyam, 1998). The exact mechanism of action is still not clear, although recent evidence from in vivo studies suggests that honey reduced the edema and plasma levels of

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proinflammatory cytokines (PGE2, IL-6, TNFa, iNOS, and COX2). Also, it has been shown that honey attenuates NFkB translocation to the nucleus and hence suppresses the Ikba degradation (Hussein et al., 2012, 2013). In real-world applications, honey has been shown to treat diaper dermatitis in infants when applied as a mixture along with olive oil and bee wax (Al-Waili, 2005). Honey was also shown to significantly reduce the symptoms of coughing in children suffering from upper respiratory tract infections (Heppermann, 2009). In adults who used honey-based ointments, 8 of 10 patients with dermatitis and 5 of 8 patients with psoriasis had significant relief from their symptoms (Al-Waili, 2003b). An interesting case report details a patient with chronic dystrophic epidermolysis bullosa (EB) who was healed with honey-impregnated dressing after 15 weeks (Hon, 2005). There are numerous clinical reports that suggest that the topical application of honey relieved pain caused by radiation-induced mucositis (Amanat et al., 2017; Charalambous et al., 2018; Co et al., 2016; Fogh et al., 2017; Samdariya et al., 2015; Yang et al., 2019). However, it was interesting to discover that honey did not interfere with radiation-induced tumor cell killing, indicating that honey can be used as a topical prophylaxis against radio/chemotherapy-induced mucositis in cancer patients (Rao et al., 2017). These examples sufficiently illustrate the usefulness of honey in regulating chronic inflammatory conditions.

Antimutagenic effects of honey Mutation and its accumulation is one such factor that leads to cancer (Martincorena and Campbell, 2015). Honey has been shown to hold antimutagenic activity (Saxena et al., 2012). It was shown to exhibit protective effects on Escherichia coli DNA that were exposed to ionizing radiations (UV or gamma) (Wang et al., 2002). It was observed that some genes (umuC, recA, and umuD) that are part of the SOS-mediated mutagenesis were downregulated, thereby protecting the cells against error-prone repair pathways. Another study used honey from various floral sources such as acacia, firewood, tupelo, buckwheat, Christmas berry, and soybean along with a honey sugar analogue against a carcinogenic heterocyclic amine, Trp-p-1 (Wang et al., 2002). An Ames test done using these showed a substantial inhibition of mutagenicity that was otherwise caused by Trp-p-1. Furthermore, the use of 30% honey as a condiment in marinades on beefsteaks and chicken meat showed a significant inhibition in the generation of heterocyclic aromatic amines (Shin and Ustunol, 2006). Thus, there are convincing studies that prove the antimutagenic activities of honey; however, an understanding of its mechanism of action is still lacking.

Antiapoptotic effects of honey Cancer encompasses two major characteristics: uncontrolled cellular proliferation and lowered cell death (Nicholson, 2000). Most often, the drugs that are used in cancer treatment induce apoptosis to circumvent this problem (Earnshaw, 1995). The programmed

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cell death, also known as apoptosis, is a complex mechanism that can be divided into three phases: induction, effector, and degradation. The initial phase involves the induction of the proapoptotic signal cascade through a series of multiprotein complexes, collectively called the death-inducing signaling complex. This step involves ceramide signaling, ROS, Bcl-2 family proteins (Bad, Bax, Bid), and overactivation of Ca2+ signaling. The second step, that is, the effector phase, is a committed step that leads to cell death and involves mitochondrion. The last stage comprises nuclear and cytoplasmic changes via chromatin and nuclear condensation, DNA fragmentation, cell shrinkage, caspase activation, and membrane blebbing. These cells at last form fragmented apoptotic bodies, which are scavenged by phagocytic cells (Earnshaw, 1995; Susin et al., 1998). The apoptosis by convention follows two pathways, namely caspase-8 (death-receptor pathways) and caspase-9 (mitochondrial pathway). A broad literature survey suggests that honey induces apoptosis in various types of cancer cell lines ( Jaganathan and Mandal, 2009, 2010; Lee et al., 2003; Pichichero et al., 2010). Honey is assumed to execute apoptosis via regulating various steps in the signaling pathways. Honey was shown to induce apoptosis in human breast, cervical, and colon cell lines via depolarization of the membrane of mitochondria, thus reducing its membrane potential ( Jaganathan and Mandal, 2009, 2010). Hence, these reports suggest that the caspase-9 pathway was involved in apoptosis by honey. Another study on human colon and glioma C6 cell lines showed that crude honey induced caspase-3 activation and PARP (Poly (ADPribose) polymerase) cleavage. This function was attributed to higher levels of phenolic and tryptophan present in the honey (Fernandez-Cabezudo et al., 2013; Jaganathan and Mandal, 2009; Lee et al., 2003). Researchers have shown that elevated levels of caspase-3, p53, and Bax protein in HCT-15 and HT-29 colon cancer cell lines favored apoptosis ( Jaganathan and Mandal, 2010). Honey administered in combination with Aloe vera extract was found to increase the expression of Bax, a proapoptotic protein, and reduce the antiapoptotic Bcl-2 protein in Wistar rats with W256 mammary carcinoma xenografts (Fernandez-Cabezudo et al., 2013; Tomasin and Gomes-Marcondes, 2011). Furthermore, two independent studies showed that honey exerts its protective effects via modulating the immune response, therefore ameliorating the hematological parameters and inducing the mitochondrial-dependent apoptotic pathway at the cellular level (Ahmed and Othman, 2017; Ahmed et al., 2017). In these studies, the Sprague-Dawley rats were fed honey at various concentrations (0.2 to 2.0 g/kg body weight). It was observed that honey induced the intrinsic apoptotic pathway via the upregulation of caspase-9 dependent signals, which includes upregulation of p53, APAF-1 (apoptotic protease activating factor 1), IFN-gamma (interferon gamma), and IFNGR1 (interferon gamma receptor-1) expression. Concurrently, honey downregulated the antiapoptotic proteins such as COX-2, TNFa, E2 (estrogen), and ESR1 (estrogen receptor 1). These studies also confirmed that honey induced only intrinsic or caspase-9 apoptotic pathways and the caspase-8 pathway was not involved. The mechanism of action of honey mainly involved apoptotic and cell cycle arrest, which in turn may comprise the antiinflammatory, estrogenic modulatory, antimutagenic, insulin, and immunomodulatory pathways (Ahmed et al., 2018; Erejuwa et al.,

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2014). There is still more to be understood, as we do not completely understand how honey can affect the caspase-8 pathway and other receptors, enzymes, and factors that are part of the cell cycle. Thus, further studies are required to understand the full potential of honey and its mechanism such that it can be used as a potential anticancer agent.

Antiproliferative effects of honey Active cell division is an imminent way for cells to replace dead cells. The cell cycle is a complex process that can be mainly distinguished into the G1, S, G2, and M phases. The cells gear up for cell division in the G1 phase, and the S phase involves the synthesis of DNA. The G2 and M phases are where cell division happens. The cell cycle is well regulated by cyclins and cyclin-dependent kinases. The transition of cells from the G1/S phases is vital for determining one’s fate if they are destined for proliferation, differentiation, quiescence, or apoptosis. Hence, a loss in regulation of the cell cycle is a hallmark of cancer (Diehl, 2002). Honey administered in Wistar rats along with Aloe vera extract reduced the expression of Ki67-LI, a novel nuclear marker of cell proliferation (Tomasin and Gomes-Marcondes, 2011). Also, honey and its flavonoid and phenolic components are reported to block the cell cycle in colon cell lines at the G0/G1 phases ( Jaganathan and Mandal, 2009). This was attributed to downregulation of key enzymes such as cyclooxygenase, ornithine decarboxylase, and kinase, thus affecting their cellular pathways. Honey has been shown to modulate p53 levels in colon cancer cell lines ( Jaganathan and Mandal, 2009, 2010). The p53 protein increases cyclin-dependent kinase (Cdk) upon DNA damage. Thus, honey suppresses or blocks the abnormal cells from dividing. Hence, it can be hypothesized that honey facilitates apoptosis via perturbations in the cell cycle and inhibition of cell growth (Benkovic et al., 2008; Jaganathan and Mandal, 2009; Lee et al., 2003; Pichichero et al., 2010).

Conclusion The pharmacological effects of honey can be the basis for developing novel therapeutics for patients suffering from cancer. Some jungle honey fragments were reported to induce chemotactic neutrophils and ROS, causing cell death (Fukuda et al., 2011). Also, a variety of Malaysian jungle honey has shown significant anticancer activity against human breast, oral, cervical, and osteosarcoma cell lines (Fauzi et al., 2011; Ghashm et al., 2010). The presence of flavonoids such as chrysin in honey has been suggested to inhibit cell proliferation and induction of apoptosis while arresting the cell cycle ( Jaganathan et al., 2010; Pichichero et al., 2010; Woo et al., 2004). The constituents of honey vary widely along geographical areas and seasons. There is still a lot to explore about how honey mediates anticancer effects. Honey is a natural antioxidant and antiinflammatory agent. There is ample evidence showing that honey can modulate multiple signaling pathways, arrest the cell cycle, inhibit lipid oxidation, and induce apoptosis (summarized in Fig. 7.1). Further investigations are required to establish the possible mechanisms and validate the clinical use of honey, either as a lone drug or as an adjuvant therapy.

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Immune system

Metastasis and angiogenesis

Free radical scavenging Antioxidative enzymes

Cancer cell proliferation Mitogenic proliferative signals

Honey

Oxidative stress Inflammation

Cell cycle regulatory proteins

Anti apoptotic proteins

Signal transduction molecules Pro apoptotic proteins

FIG. 7.1 Molecular targets mediated by honey for anticancer properties. Symbols depict # ¼ decrease and " ¼ increase.

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Tomasin, R., Gomes-Marcondes, M.C., 2011. Oral administration of Aloe vera and honey reduces Walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue. Phytother. Res. 25 (4), 619–623. Tomasin, R., de Andrade, R.S., Gomes-Marcondes, M.C., 2015. Oral administration of Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) and honey improves the host body composition and modulates proteolysis through reduction of tumor progression and oxidative stress in rats. J. Med. Food 18 (10), 1128–1135. Tonks, A.J., Cooper, R.A., Jones, K.P., Blair, S., Parton, J., Tonks, A., 2003. Honey stimulates inflammatory cytokine production from monocytes. Cytokine 21 (5), 242–247. Tonks, A.J., Dudley, E., Porter, N.G., Parton, J., Brazier, J., Smith, E.L., Tonks, A., 2007. A 5.8-kDa component of manuka honey stimulates immune cells via TLR4. J. Leukoc. Biol. 82 (5), 1147–1155. van Acker, S.A., van den Berg, D.J., Tromp, M.N., Griffioen, D.H., van Bennekom, W.P., van der Vijgh, W.J., Bast, A., 1996. Structural aspects of antioxidant activity of flavonoids. Free Radic. Biol. Med. 20 (3), 331–342. Vandamme, L., Heyneman, A., Hoeksema, H., Verbelen, J., Monstrey, S., 2013. Honey in modern wound care: a systematic review. Burns 39 (8), 1514–1525. Wang, X.H., Andrae, L., Engeseth, N.J., 2002. Antimutagenic effect of various honeys and sugars against Trp-p-1. J. Agric. Food Chem. 50 (23), 6923–6928. Woo, K.J., Jeong, Y.J., Park, J.W., Kwon, T.K., 2004. Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem. Biophys. Res. Commun. 325 (4), 1215–1222. Yang, C., Gong, G., Jin, E., Han, X., Zhuo, Y., Yang, S., Song, B., Zhang, Y., Piao, C., 2019. Topical application of honey in the management of chemo/radiotherapy-induced oral mucositis: a systematic review and network meta-analysis. Int. J. Nurs. Stud. 89, 80–87.

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Curcumin in cancer prevention and therapy Meher Un Nessaa,b, Fazlul Huqc E N V I R O N ME N T A L SC I E NC E D I S C I P L I N E , LI FE SCIENCE SCHOOL, KHULNA UNIVERSITY, KHULNA, BANGLADESH b DISC IPLINE OF PATHOLOGY, SC HOOL OF MEDIC AL SCI ENCES , FACULTY O F MEDICINE AND HE ALTH, THE UNIVERSITY OF SYDNEY, SYDNEY, N SW, AUSTRALIA c D I S C I PL I NE O F PA T HO L O G Y, S C H OO L O F M E DICAL SC IENCE S, FACULTY O F MEDI CINE AND HEALTH, THE UNIVERSITY OF SYDNEY, SYDNEY, NS W, AUSTRALIA a

Introduction With more than 10 million new cases diagnosed every year, cancer is one of the most dreaded diseases of our time. Despite significant innovations in the development of cancer therapies over the past several decades, the global burden of cancer continues to increase and cancer has become one of the most devastating diseases worldwide. Therefore, cancer prevention has become an important avenue through which the fight against cancer could be feasible (Sarkar and Li, 2007). At the very outset, we must acknowledge that cancer is caused by both internal factors (such as inherited mutations, hormones, and immune conditions) and environmental/acquired factors (such as tobacco, diet, radiation, and infectious organisms). Although hereditary factors cannot be modified, lifestyle and environmental factors are potentially modifiable. The lesser hereditary influence of cancer and the modifiable nature of the environmental factors point to the preventability of cancer (Anand et al., 2008). Thus, the two most important ways to reduce cancer risk are the avoidance of cancer-causing biological, chemical, and physical agents and the habitual consumption of diets high in foods that can provide protection against cancer (Amin et al., 2009). As cancer is a result of the dysregulation of as many as 500 different gene products, the inhibition of a single gene product or cell signaling pathway is unlikely to prevent or treat cancer. It is now time to find the magic remedy by targeting the multiple signaling steps of carcinogenesis.

Carcinogenesis, chemoprevention, and plant-derived products Carcinogenesis is generally recognized as a multistep process in which distinct molecular and cellular alterations occur. It is the result of too many aggressive, invasive cells being Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00008-9 © 2020 Elsevier Inc. All rights reserved.

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present in the wrong place at the wrong time. Thus, although molecular lesions in genes that regulate the cell cycle might enhance carcinogenesis, the tumorigenic process also affects the normal relationships between epithelial cells and their underlying stromal cells (Sporn and Suh, 2002). The invasive and metastatic carcinoma is the final stage of many dysfunctional steps at both the cellular and tissue level. This complex process will probably require many pharmacological agents to prevent end-stage disease. The current thought is that it would be nice to have a single “magic bullet” that would either prevent carcinoma or treat metastatic malignancy. A cancer chemoprevention strategy to decrease the incidence of cancer was first suggested by Dr. B. Michael Sporn; it was a novel field in cancer research (Sporn, 1976). The term “chemoprevention” is broadly used to indicate the ability of a molecule not only to prevent but also to cure cancer. According to a more modern and complete definition, chemoprevention includes the use of natural or pharmacological agents to suppress, arrest, or reverse carcinogenesis at its early stages (Sporn and Suh, 2002; Russo, 2007). As approximately 30%–40% of cancer incidents can be preventable by having a healthy diet, regular physical activity, and maintenance of optimum body weight, and more than 20% by consuming vegetables and fruits, the attribute “chemopreventive” has also been associated to a lifestyle (Russo, 2007; Amin et al., 2009). In studies involving human subjects, safety is always a primary consideration, particularly patients without evidence for obvious cancer. Because patient accrual to chemoprevention trials is sometimes a challenge, partly due to the toxicity of the pharmaceuticals investigated, an ideal chemopreventive agent should be nontoxic, effective at lower doses, economical, and easily available (Amin et al., 2009). In recent years, most of the nontoxic chemical substances used in cancer chemoprevention are natural phytochemicals— nonnutritive components in the plant-based diet—because of their potential ability to suppress cancers as well as reduce the risk of cancer development (Surh, 2003). Based on the stages of cancer development targeted by a chemopreventive agent, they can be categorized either as a cancer-blocking agent that blocks the cancer initiation step or as a cancer-suppressing agent that halts or retards the promotion and progression of precancerous cells into malignant ones. As cancer is a result of the dysregulation of as many as 500 different gene products, the inhibition of a single gene product or cell signaling pathway is unlikely to prevent or treat cancer (Kunnumakkara et al., 2008). Those that can act on all stages of cancer development fall into both categories, which is very common for plant-derived phytochemicals (Shen et al., 2005).

Curcumin: A super magical chemopreventive and therapeutic agent Curcumin, a polyphenol, is known as diferuloylmethane (C21H20O6) (Fig. 8.1). It has a molecular weight of 368.37 g/mol and is a member of the ginger family Zingeberacea that has been extracted from the dried ground rhizome of the perennial herb curcuma species (Curcuma longa), a spice or dietary flavoring agent commonly used in Asian cooking

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O

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O

OH

HO OCH3

H3CO

FIG. 8.1 Structure of curcumin.

(HemaIswarya and Doble, 2006; Sa and Das, 2008). It is safe and well tolerated, even at very high doses. According to a joint FAO/WHO report on food additives, the recommended maximum daily intake of curcumin is 0–1 mg/kg body weight with no adverse effects (WHO, 2000). Although the broad medicinal properties of curcumin have been known for centuries, its promising chemopreventive and potentially chemotherapeutic properties have become the focus of renewed interest only recently (Deorukhkar et al., 2007). Curcumin can suppress proliferation and induce apoptosis in tumor cells. The diverse activities of curcumin in terms of antioxidant, antiproliferative, and antiangiogenic functions are mediated through multiple signaling pathways (Kunnumakkara et al., 2008; Reuter et al., 2008). The molecular targets of curcumin also include transcription factors, growth factors, cytokines, enzymes, and other gene products (Hussain and Harris, 2007; Goel et al., 2008). Tumorigenesis is a multistep process where the initiation and establishment of a tumor is activated by any of various environmental carcinogens, inflammatory agents, and tumor promoters through modulation of the transcription factors, antiapoptotic proteins, proapoptotic proteins, protein kinases, cell cycle proteins, cell adhesion molecules, and growth factor signaling pathways. The development of tumors arises as a consequence of dysregulated proliferation and suppression of apoptosis, and each of these primary defects provides an obvious opportunity for clinical intervention (Kasibhatla and Tseng, 2003). It is hoped that greater insights into the field of apoptosis and cancer will uncover new and effective strategies to tackle the complexity of treatment and even the onset of cancer. This chapter reviews the current studies regarding hallmarks of cancer and the molecular activity of curcumin on numerous cellular pathways and molecular targets, not only for the prevention of cancers, but also for treatment.

Hallmarks of cancer and molecular targets for chemoprevention and treatment Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells are distinct from normal cells in six different ways and these characteristics are shared by all cancers: self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion, and metastasis (Hanahan and Weinberg, 2000).

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The ability of tumor cell populations to expand in number is determined by both the rate of cell proliferation and the rate of cell death. Cell proliferation and cell death are two diametrically opposed cellular fates that are linked and interdependent (Evan and Vousden, 2001; Lowe et al., 2004). In normal cells, there is a finely controlled balance between growth-promoting and growth-restraining signals, such that proliferation occurs only when required. In tumor cells, this process is disrupted so continued cell proliferation would occur and loss of differentiation may also be found. In addition, the process of programmed cell death existing in normal cells may no longer operate (Hahn and Weinberg, 2002). In other words, a normal cell becomes malignant when cellular proliferation is no longer under normal growth control. There are other characteristics that cancer cells may acquire, including angiogenesis, metastasis, and suppression of apoptosis. But uncontrolled proliferation of the cell lies at the heart of the disease. Therefore, to understand cancer we need to have clear knowledge on cell proliferation and control so that therapeutic targets that have the highest chance of successful tumor regression can be chosen.

Cell cycle and curcumin The process of dividing a cell and replicating it can be described as a series of coordinated events that composes a “cell division cycle.” The mammalian cell cycle has been divided into a series of sequential phases. The G1, S, G2, and M phases are sequentially transitioned in response to growth factor or mitogenic stimulation. Cell cycle progression is a highly ordered and tightly regulated process that involves multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity (Park and Lee, 2003). These regulations are maintained by multiple interactions between molecules in normal cells. In addition, cells are equipped with signaling pathways that can sense unfavorable conditions for proliferation and can directly block cell division (Norbury and Nurse, 1992; Hartwell and Kastan, 1994; Nurse et al., 1998). Two types of cell cycle control mechanisms are recognized: (i) a cascade of protein phosphorylations that relays a cell from one stage to the next, and (ii) a set of checkpoints that monitors the completion of critical events and delays progression to the next stage, if necessary (Sa and Das, 2008). The heart of the regulatory apparatus during cell cycle progression is a family of enzymes named cyclin dependent kinases (CDKs), which are highly regulated (Norbury and Nurse, 1992; Hartwell and Kastan, 1994; Nurse et al., 1998; Park and Lee, 2003). Kinase activation generally requires association with a second subunit called a “cyclin” that is transiently expressed at the appropriate period of the cell cycle (Sa and Das, 2008). CDKs and their cyclin partners are positive regulators or accelerators, whereas important negative regulators are cyclin dependent kinase inhibitors (CKIs). By direct association with CDK, two families of CKIs—INK (p15, p16, p18, and p19) and CIP/ KIP (p21, p27, and p57)—can negatively regulate CDK activity (Sherr and Roberts, 1999; Sherr, 2000). Dysregulation of the cell cycle checkpoints and overexpression of the growth-promoting cell cycle factors cyclin D1 and CDKs are associated with tumorigenesis. A significant increase in cyclin D1 has been observed in all types of human ovarian

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cancer (Barbieri et al., 1999) because it occurs in 60% of breast cancers, 40% of colorectal cancers, 40% of squamous carcinoma of the head and neck, and 20% of prostate cancers (Weinstein et al., 1997; Han et al., 1998; Sgambato et al., 1998). Curcumin is a good choice to prevent and treat cancer because it inhibits progression of the cell cycle by downregulating the expression of cyclin D1 at the transcriptional and posttranscriptional levels. Curcumin can do this by suppressing the activity of NF-κB, which ultimately downregulates the expression of cyclin D1 (Aggarwal and Shishodia, 2006). This decrease in the formation of the cyclin D1/CDK4 holoenzyme complex suppresses proliferation and induces apoptosis. Curcumin also induces G0/G1 and/or G2/M phase cell cycle arrest by upregulated CDK inhibitors such as p21/CIP1/WAF1 and p27/KIP1 and downregulated cyclin B1 and CDC2 (Park et al., 2002). The expression of p21 is also directly induced by p53 (Sherr, 1994; Park and Lee, 2003). Along with p53-independent G2/M phase arrest, curcumin also induces this p53-dependent apoptosis in various cancers (Choudhuri et al., 2005; Dhillon et al., 2008; Sa and Das, 2008).

Cell death (apoptosis) and curcumin The cells of a multicellular organism are highly organized and tightly regulated, not simply by controlling the rate of cell division but also by controlling the rate of cell death. If cells are no longer needed, they commit to suicide by activating an intracellular death program. This process is therefore called programmed cell death, more commonly known as apoptosis. A cell that undergoes apoptosis dies neatly without damaging its neighbors through two main pathways: the extrinsic cytoplasmic pathway and the intrinsic mitochondrial pathway (Park and Lee, 2003). Each pathways requires specific triggering signals to begin an energy-dependent cascade of molecular events. The extrinsic pathway is triggered through the Fas receptor, which is in the tumor necrosis factor (TNF) superfamily. Fas is also known as Apo-1 or CD95. The intrinsic pathway leads to the release of cytochrome-C, but both pathways converge onto a final common pathway. Each pathway activates its own initiator caspase (8, 9, 10), which in turn will activate the executioner caspase-3 (Elmore, 2007). Activation of the JNK (c-Jun N-terminal kinases) signaling pathway is frequently observed in apoptosis. A number of apoptotic molecules are targets for JNK-mediated phosphorylation including p53, c-Myc, and the antiapoptotic Bcl-2 proteins (Bcl-2 and Bcl-xL) (Fuchs et al., 1998a, b; Noguchi et al., 1999; Yamamoto et al., 1999). Each of these proteins is capable of regulating the release of cytochrome c, the key event in the activation of caspases (Tournier et al., 2000). Cell proliferation and cell death are two diametrically opposed cellular fates that are fully linked but interdependent (Evan and Vousden, 2001; Lowe et al., 2004). Like defective cell progression, defective apoptosis (programmed cell death) also represents a major causative factor in the development and progression of cancer. The ability of cancer cells to evade this programmed cell death is a major characteristic that enables them to undergo uncontrolled growth. The efficiency of chemotherapy in killing such cells depends on the successful induction of apoptosis (Melet et al., 2008). The divergent

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antitumor effects of curcumin are dependent on its pleiotropic molecular effects. These include the regulation of signal transduction pathways and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors and, in turn, the cellular expression profiles. For example, curcumin shows its antitumor activity by downregulating the expression of the apoptosis suppressor proteins Bcl-2, and Bcl-xL and upregulating the expression of proapoptotic proteins Bax and AIF. This is followed by rapidly generating reactive oxygen species (ROS), activating caspase 3-independent apoptosis, activating mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Curcumin also activates caspase-7 and caspase-9 and induces polyadenosine-50diphosphateribose polymerase (PARP) cleavage (Aggarwal and Shishodia, 2006; Shishodia et al., 2007; Singh and Singh, 2009). As the development of tumors arises as a consequence of dysregulated proliferation and suppression of apoptosis, each of these primary defects provides an obvious opportunity for clinical intervention (Kasibhatla and Tseng, 2003). It is hoped that greater insights into the field of apoptosis and cancer will uncover new and effective strategies to tackle the complexity of tumors, their treatment, and chemoresistance.

Molecular mechanisms of curcumin action Mitochondrial activation Mitochondria play a central role in the process of apoptosis. The intrinsic pathway of apoptosis involves the activation of proapoptotic members of the Bcl-2 family that exert their function through mitochondria. Mitochondrial involvement is well established in curcumin-induced apoptosis (Su et al., 2006; Tan et al., 2006; Shankar and Srivastava, 2007; Cheah et al., 2009). Curcumin induces caspase-dependent apoptosis by releasing cytochrome c from mitochondria, which causes the activation of caspase 3 and simultaneous PARP cleavage (Ravindran et al., 2009). Curcumin also induces caspase 3-independent apoptosis by the release of AIF from the mitochondria to the cytosol and nucleus, which is a consequence of curcumin-induced rapid ROS generation. Mitochondrial hyperpolarization is a prerequisite for curcumin-induced apoptosis and mtDNA damage is the initial event triggering a chain of events leading to apoptosis (Cao et al., 2007). Exposure to curcumin causes a transient elevation of mitochondrial membrane potential (MMP), which ultimately disrupts mitochondrial membrane potential (MMP) followed by cytochrome c release into the cytosol (Tan et al., 2006). By opening of the permeability transition pore, curcumin also increases mitochondrial membrane permeability, resulting in a loss of membrane potential and inhibition of ATP synthesis. Curcumin targets proliferative cells more efficiently than differentiated cells and induces apoptosis via mitochondrial pathways. Cytoprotective effects of curcumin might be mediated by the Bcl-2-mitochondria-ROS-iNOS pathway (Chen et al., 2006).

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Caspase activation Caspases, or cysteine-aspartic proteases, are a family of cysteine proteases; they are among the main executors of the apoptotic process (Alnemri et al., 1996). One of the hallmarks of apoptosis is the cleavage of chromosomal DNA into nucleosomal units. The caspase activation plays an important role in this process by activating DNases, inhibiting DNA repair enzymes such as poly (ADP-ribose) polymerase (PARP), and breaking down structural nuclear proteins, which causes chromatin condensation and nuclear fragmentation commonly observed in apoptotic cells (Fulda, 2008). In the mitochondrial pathway, caspase activation is triggered by the formation of a multimeric Apaf-cytochrome c complex that in turn activates procaspase 9. Activated initiator caspase 9 will then cleave and activate downstream effector caspases such as caspases 3, 6, and 7. This pathway is regulated at several steps, including the release of cytochrome c from the mitochondria, the binding and hydrolysis of dATP/ATP by Apaf-1, and the inhibition of caspase activation by the proteins that belong to the inhibitors of apoptosis (IAP) (Ravindran et al., 2009). Curcumin induces apoptosis through the mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, caspase-3 activation, and poly-(ADPribose) polymerase (PARP) cleavage. Curcumin also causes DNA damage and endoplasmic reticulum (ER) stress through the activation of caspase-3 (Anto et al., 2002; Lin et al., 2008; Shehzad et al., 2010). Again, curcumin induces the cleavage of procaspases 3, 8, and 9 and the release of cytochrome c from mitochondria, whereas it activates caspases 3 and 8 but not caspase 9, supporting the rationale that apoptosis occurs via a membrane-mediated mechanism (Bush et al., 2001; Gao et al., 2005; Kang et al., 2006). In addition, curcumin inhibits the expression of inhibitors of apoptosis (IAP) proteins, which selectively bind and inhibit the activation of caspases 3, 7, and 9. Therefore, as an inhibitor of IAP, curcumin has great potential in the treatment of malignancy (Dean et al., 2007; Kunnumakkara et al., 2008; Ravindran et al., 2009; Tharakan et al., 2010).

Oxidative stress A key feature that distinguishes cancer cells from normal ones is that they are subject to a greater oxidative stress (Szatrowski and Nathan, 1991; Toyokuni et al., 1995). Cancer cells have higher levels of reactive oxygen species (ROS) (than normal cells) that are in turn responsible for the maintenance of the cancer phenotype (Gibellini et al., 2010). While ROS have been found to be deleterious to cells, they also function as signaling molecules that induce adaptive responses to stress or an adverse microenvironment (Cui, 2012). While baseline or, at least, controlled ROS levels exert a prominent prosurvival effect in cancer cells, high levels of ROS cause cellular damage and ultimately apoptosis by irreversibly damaging cellular macromolecules (Dalle-Donne et al., 2003) or by modulating redox-sensitive signaling proteins at the levels of transduction or transcriptional regulation (or both) (Trachootham et al., 2008). Production of ROS also leads to the depolarization of the mitochondrial membrane and releases proapoptotic molecules from mitochondria into the cytosol, thus inducing apoptosis (Shehzad et al., 2010). In addition,

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the cytochrome-c release from the mitochondrial membrane results in an increased level of cytochrome c at the cytoplasm and nucleus, which induces apoptosis through a mitochondrial permeability transition (Wang, 2001). Curcumin induces the rapid depletion of glutathione (GSH). This rapid depletion increases the ROS levels and enhances scavenging of peroxides in the cytosol as well as in the mitochondria (Armstrong et al., 2002). Apoptosis-inducing factor (AIF) is a mitochondrial apoptogenic protease that, in response to some apoptotic stimulus, translocates from mitochondria to cytosol and further to the nucleus. Within the nucleus, AIF triggers chromatin condensation and large-scale DNA fragmentation (Lorenzo and Susin, 2004). Curcumin-induced rapid ROS generation causes the release of AIF from the mitochondria to the cytosol and nucleus, leading to caspase 3-independent apoptosis (Ravindran et al., 2009). ROS generation by curcumin also releases endonuclease G (EndoG) into the cytosol and nucleus, where they induce caspase 3-independent apoptosis (Thayyullathil et al., 2008). The curcumin mechanism of ROS-triggered cell death also involves the p53 tumor suppressor gene. Moreover, curcumin has the ability to protect lipids, hemoglobin, and DNA against oxidative degradation, which can reduce the side effect of chemotherapy in cancer treatment (Ravindran et al., 2009; Shehzad et al., 2010).

Direct DNA damage Changes in the normal double helical conformation of DNA include structural distortions that interfere with replication and transcription as well as point mutations that disrupt base pairing and exert damaging effects on future generations through changes in the DNA sequence. Minor damage can often be repaired, whereas unrepairable extensive damage finally induces apoptosis. By producing ROS and lipid peroxidation and by inhibiting DNA repair enzymes, curcumin induces a dose- and time-dependent increase in DNA damage to both the mitochondrial and nuclear genomes (Cao et al., 2006; Lu et al., 2009).

P53/p21 pathway The transcription factor p53 not only plays a central role in the cellular stress response pathways, but it also promotes apoptosis through a variety of mechanisms. It is also involved in cell signal transduction, cellular response to DNA damage, genomic stability, and cell cycle control; this makes it responsible for protecting cells from tumorigenic alterations (Levine, 1997; Haupt et al., 2003; Shehzad et al., 2010). A major factor affecting the loss of apoptotic function in cancer cells is p53 gene mutation (Levine, 1997). The p53 role in apoptosis by curcumin is tissue- and cell-specific. Curcumin selectively increases p53 expression at the G2 phase of cancer cells, followed by the induction of p21cip1/waf-1 and p27kip-1 that prevents the inhibition of cyclin/cdk complexes in the ternary complex as well as blocks the cell cycle progression through phosphorylation (Choudhuri et al., 2005; Sa and Das, 2008).

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NF-κB and AP-1 signaling pathways Numerous intracellular signal transduction pathways come together with the activation of transcription factors NF-κB and AP-1, which regulate target gene expression both independently and coordinately (Surh, 2003). These ever-present eukaryotic transcription factors, which mediate the pleiotrophic effects of both external and internal stimuli in the cellular signaling cascades, could be the prime targets of chemoprevention. Curcumin effectively blocks AP-1 and NF-κB signaling pathways and enhances apoptosis in many cancer cell lines (Zheng et al., 2004; Jung et al., 2005). The most important transcription factor, NF-κB, widely acts as a regulator of genes that control cell proliferation and cell survival (Shehzad et al., 2010). As a majority of all solid tumors are driven by NF-κB as a player, most cancer preventative agents are believed to be NF-κB inhibitors (Banerjee et al., 2010). Aberrant activation of NF-κB can provide protection against apoptosis and stimulate proliferation of malignant cells, and its overexpression is causally linked to phenotypic changes that are characteristic of neoplastic transformation. Activation of NF-κB occurs in response to a wide variety of stimuli such as cytokines; growth factors; physiological, physical, and oxidative stress; and certain pharmacological drugs and chemicals (Solomon et al., 2008). The convergent step in signal-induced activation of NF-κB is the phosphorylation of IκBα, which is carried out by IKK, leading to its ubiquitination and degradation. Once IκBα is degraded, the active NF-κB is translocated into the nucleus. The inhibitory effect of curcumin on NF-κB activation is due to the inhibition of the IKK activity signaling complex responsible for the phosphorylation of IκB, thereby blocking the improper activation of NF-κB and inducing apoptosis ( Jobin et al., 1999; Plummer et al., 1999; Shehzad et al., 2010; Kim et al., 2011). AP-1 is another transcription factor that regulates the expression of genes involved in cellular adaptation, differentiation, and proliferation. Functional activation of AP-1 is associated with malignant transformation and also tumor promotion (Dong et al., 1995; Bode et al., 2001; Surh, 2003) AP-1 is synchronized by various stimuli, proinflammatory cytokines, growth factors, oxidative stress, and tumor promoters. When AP- 1 is activated, it binds to TPA response elements (TRE) or cAMP response elements (CRE) in the promoter region of the target genes (Shehzad et al., 2010). Its association with the proliferation and transformation of tumor cells drives through the activation of the stress-activated C-Jun N-terminal kinase (JNK). Activation of JNK and p38 MAPK phosphorylation enhances the activity of c-Jun and ATF2 proteins, which in turn leads to the activation of AP-1 target genes. JNK is also associated with PI3K in the upregulation of AP-1 activity (Funakoshi-Tago et al., 2003). Curcumin inhibits the activation of both AP-1 and JNK. Curcumin also inhibits c-Fos transcription factor activation by the inhibition of extracellular signal-regulated kinase (ERK) and JNK (Kunnumakkara et al., 2008; Shehzad et al., 2010).

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Akt (protein kinase B) pathway Akt, a serine/threonine kinase, is a vital enzyme in signal transduction pathways involved in cell proliferation, apoptosis, and angiogenesis (Ravindran et al., 2009). Apoptosis is negatively regulated by the activity of the phosphatidylinositol 30 -kinase to the Akt kinase signaling cascade, which functions as a potent prosurvival signal in a variety of tumor types (Kasibhatla and Tseng, 2003). Akt potentiates the activity of NF-κB by accelerating the degradation of its endogenous inhibitor, IκB (Kane et al., 1999). This can lead to elevation in the expression of its target genes, including the antiapoptotic Bcl-2 protein A1, TRAF1, and TRAF-2, and the caspase inhibitors c-IAP1 and c-IAP2 (Zong et al., 1999; Kasibhatla and Tseng, 2003). Such activities of NF-κB explain the frequently observed elevation of constitutive NF-κB activity in many drug-resistant tumor cells (Rayet and Gelinas, 1999). In addition, mTOR, a large class IV PI-3 kinase family member, functions to arrest the cell cycle in the G1 phase. mTOR regulates Akt activity, a crucial downstream effector in the PI-3K-PTEN pathway that controls cell proliferation and survival. Targeting this function of mTOR also has therapeutic potential (Shinojima et al., 2007). Thus compounds able to suppress this prosurvival Akt pathway can be potential candidates to prevent cancer and overcome drug resistance. Curcumin inhibits Akt, mTOR, and their downstream substrates (Yu et al., 2008; Johnson et al., 2009).

STAT signaling The STAT protein (signal transducer and activator of transcription) regulates many aspects of growth, survival, and differentiation in cells. STAT proteins remain latent in the cytoplasm, requiring phosphorylation for nuclear translocation. Extracellular binding of cytokines induces activation of the intracellular Janus kinase (JAK) that phosphorylates a specific tyrosine residue in the STAT protein that promotes the dimerization of STAT monomers. This phosphorylated dimer is then actively transported in the nucleus, where it binds to a specific DNA sequence (Darnell, 1997). STATs are constitutively activated in a variety of tumors and the agents that can suppress STAT phosphorylation have potential for the prevention and treatment of cancer. Curcumin inhibited both inducible and constitutive STAT3 activation and its nuclear translocation by inhibiting JAK-2 phosphorylation and also interferon (IFN)-α-induced STAT1 phosphorylation, whereas it has no effect on STAT5 phosphorylation (Bharti et al., 2003).

Nrf2 signaling Other than suppressing tumor promotion or progression, another important approach to chemoprevention is to block the DNA damage caused by carcinogenic insult—the initiation stage of carcinogenesis. The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) antioxidant response pathway is “the primary cellular defense against the cytotoxic effects of oxidative stress.” This redox-sensitive basic leucine zipper transcription factor Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the

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expression of a number of cytoprotective antioxidant genes by binding with their ARE (antioxidant-responsive element) site ( Jaramillo and Zhang, 2013). These genes encode cellular antioxidants such as glutathione peroxidase, gamma-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and glutathione. This phase II enzyme induction system is an important component of the cellular stress response in which a diverse array of electrophilic and oxidative toxicants can be removed from the cell before any damage is done to the DNA (Surh, 2003). The cytosolic actin-binding protein KEAP1 (Kelch-like ECH-associated protein 1), a negative regulator of nrf2, suppresses the transcriptional activity of nrf2 by retaining the transcription factor in the cytoplasm and hampering its nuclear translocation (Surh, 2003). Curcumin stimulated the activation of Nrf2 by inactivating the Nrf2-Keap1 complex, which can increase nuclear translocation of Nrf2 and its DNA binding activity, which is associated with a significant increase in the activity and expression of HO1. The antiproliferative effect of curcumin is also considerably linked to its ability to induce HO1 expression (Dickinson et al., 2003; Pae et al., 2007; Ravindran et al., 2009).

β-Catenin β-Catenin is another significant target of chemoprevention. This multifunctional protein is a component of the cell-cell adhesion machinery (Kemler, 1993; Aberle et al., 1996). It is a component of the evolutionarily conserved WNT signaling pathway, and in addition to normal developmental processes, is also involved in tumorigenesis (Fodde and Brabletz, 2007; MacDonald et al., 2009). The cytoplasmic β-catenin undergoes rapid turnover by a large multiprotein complex that consists of glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), axin, and conductin. GSK-3β—either directly or through activation of APC—phosphorylates β-catenin, leading to ubiquitylation followed by proteasomal degradation of β-catenin (Rubinfeld et al., 1996; Hart et al., 1998). In response to WNT signaling as well as signaling by several growth factors, β-catenin stabilizes in the cytoplasm, therefore it can escape the degradation pathway. GSK-3β can be inactivated by phosphorylation of serine-9, either through WNT signaling or through activation of the PI3K-AKT pathway (Grimes and Jope, 2001). Once β-catenin is stabilized, it translocates into the nucleus and interacts with the T-cell factor-lymphoid enhancer factor (TCFLEF) family of transcription factors (Morin, 1999; Novak and Dedhar, 1999). The b-catenin/ TCF-LEF complex regulates the proto-oncogene c-myc, the G1/S-regulating cyclin D1, the AP-1 transcription factors, c-jun, fos-related antigen 1 (fra-1), and the urokinase type plasminogen activator receptor. Curcumin is an excellent inhibitor of b-catenin/TCF-LEF and, hence, reduces b-catenin/TCF signaling in cancer cells (Mann et al., 1999; Shehzad and Lee, 2010). Moreover, curcumin reduces the cellular levels of β-catenin through caspasemediated cleavage of the protein ( Jaiswal et al., 2002; Surh, 2003). Furthermore, curcumin induces cell cycle arrest as well as apoptosis through inhibition of Wnt signaling, P13K-AKT activation, and the cell-cell adhesion pathway (Shehzad et al., 2010).

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Growth factors Proliferation of tumor cells is crucially dependent on growth factors and some cytokine signaling receptors. For example, epidermal growth factor (EGF) and its receptor (EGFR1), human epidermal growth factor receptor (HER2), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor (TNF), insulin growth factor (IGF)-1, androgen receptors (AR), AR-related cofactors, and others have been associated with cell proliferation. VEGF and FGF play major roles in angiogenesis and tumor growth and are overexpressed in many cancers. Thus, suppression of the expression of these growth factors or their receptors or postreceptor signaling is needed to suppress tumor growth. Agents that inhibit expression of these growth factors and/or their receptors can play a vital role in the treatment of cancer. Curcumin has been shown to modulate the expression and activity of these growth factors. The other growth factors that are inhibited by curcumin include connective tissue growth factor, hepatocyte growth factor, nerve growth factor, tissue factor, and transforming growth factor-b (Aggarwal et al., 2007a, b; Binion et al., 2008; Kunnumakkara et al., 2008).

Enzymes Curcumin can modulate both the expression and activity of some enzymes that are directly or indirectly involved in the onset of different stages of cancer. Targeting these enzymes, curcumin can be one the most magical drugs for the prevention and treatment of cancer, possibly even overcoming drug resistance in cancer treatment.

Ornithine decarboxylase The chemopreventive effect of curcumin is due to the hyperproduction of ROS, which in turn induces apoptosis in tumor cells. Curcumin treatment reduces enzyme activity and protein expression of ornithine decarboxylase (ODC). Overexpression of ODC reduces curcumin-induced apoptosis, which leads to a loss of mitochondrial membrane potential through reducing the intracellular ROS. Moreover, ODC overexpression prevents cytochrome c release and the activation of caspase-9 and caspase-3 following curcumin treatment (Okazaki et al., 2005; Liao et al., 2008; Ravindran et al., 2009).

Thioredoxin reductase Thioredoxin reductase (TrxR), as part of a major thiol regulating system, allows the redox metabolism to adjust to cellular requirements. Three different TrxR isoenzymes—TrxR1 as cytosolic, TrxR2 as mitochondrial, and TrxR3 as a testis-specific thiol regulator—are essential mammalian selenocysteine (Sec)-containing flavoenzymes with a -Gly-CysSec-Gly active site. This selenocysteine is essentially involved in the catalytic cycle of TrxR and thus represents an attractive binding site for inhibitors (Urig and Becker, 2006). TrxRs are the only enzymes catalyzing the NADPH-dependent reduction of the active site

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disulfide in thioredoxins (Trxs), which play essential roles in substrate reductions, defense against oxidative stress, and redox regulation by thiol redox control (Ravindran et al., 2009). TrxR can scavenge ROS and directly inhibit proapoptotic proteins such as apoptosis signal-regulating kinase 1 (ASK1). Many tumor cells have elevated TrxR levels and TrxR has been shown to play a major role in drug resistance. Inhibition of TrxR and its related redox reactions thus contributes to a successful single, combinatory, or adjuvant cancer therapy. Curcumin inhibits TrxR1 activity in Trx-dependent disulfide to induce apoptosis in cancer cells (Fang et al., 2005; Urig and Becker, 2006).

COX and LOX COX is a key enzyme responsible for the conversion of arachidonic acid to prostaglandins and thromboxanes. The two known forms of COX are referred to as COX-1 and COX-2. COX-2 is the inducible form of COX; overexpression of this has a critical role in tumor promotion and carcinogenesis, for example in colon tumors (Shehzad et al., 2010). Curcumin modulates both the expression and the activity of these enzymes. In colon carcinogenesis, curcumin inhibits COX-2 gene expression, but not COX-1. Curcumin can do this by inhibiting the inhibitor of the kappa B kinase (IKK) signaling complex that is responsible for the phosphorylation of the inhibitor of kappa B (IκB) and thereby blocking improper activation of NF-κB. In human colon epithelial cells, curcumin has been shown to inhibit COX-2 initiation by the colon tumor promoters TNF through the inhibition of NF-κB (Plummer et al., 1999; Goel et al., 2001; Ravindran et al., 2009). Curcumin also regulates the eicosanoid pathway involving COX and LOX (Lipoxygenase). Curcumin regulates 5-LOX and COX-2 predominantly at the transcriptional level and, to a certain extent, the posttranslational level (Aggarwal et al., 2006; Rao, 2007).

Protein kinase Another important group of enzymes linked with tumorigenesis is the serine/threonine and/or tyrosine protein kinase. Such as mitogen-activated protein kinases (MAPK) e.g. c-jun N-terminal kinase (JNK) and P38 MAPK are responsive to stress stimuli and are involved in cell differentiation and apoptosis. Curcumin suppresses the activity of several of these kinases. Curcumin’s time- and dose-dependent induction of apoptosis is also accompanied by reduced phosphorylation and activation of JNK and p38 MAPK as well as inhibition of constitutive NF-κB transcriptional activity (Collett and Campbell, 2004; Johnson and Mukhtar, 2007). Another heterotrimeric serine/threonine protein kinase named AMP-activated protein kinase (AMPK) is strongly activated by curcumin and thus induces cell death. Stimulation of AMPK by curcumin downregulates peroxisome proliferator-activated receptor-gamma (PPAR-γ) and decreases COX2 expression, which in turn affects the proliferation rate (Pan et al., 2008). Curcumin also can inhibit protein kinase A (PKA), protein kinase C (PKC), protamine kinase (cPK), phosphorylase kinase (PhK), autophosphorylation-activated protein kinase (AK), and pp60c-src tyrosine kinases (Liu et al., 1993; Kunnumakkara et al., 2008).

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Proteasome Ubiquitin-proteasome systems are protein complexes located in the nucleus and the cytoplasm; they are the primary sites for protein degradation in mammalian cells (Peters et al., 1994; Lodish et al., 2004). Curcumin disrupts ubiquitin proteasome system (UPS) function by the direct inhibition of enzyme activity of the proteasome’s 20S core catalytic component. The direct inhibition of proteasome activity also causes an increase in the half-life of IκBα that ultimately leads to the downregulation of NF-κB activation, thus activating the apoptotic pathway (Shishodia et al., 2007; Ravindran et al., 2009). Other important enzymes that are downregulated by curcumin include arylamine N-acetyltransferases-1, ATFase, APTase, desaturase, DNA polymerase, NAD(P)H dehydrogenase quinine (NQO)1, phospholipase D, telomerase, tissue inhibitor of metalloproteinase (TIM)-3, farnesyl-protein transferase (FPTase), matrix metalloproteinase (MMP)-9, inducible nitric oxide synthase (iNOS), and others. The enzymes that are upregulated by curcumin treatment include src homology 2 domain-containing tyrosine, hemoxygenase (heme)-1, glutathione-S-transferase (GST), and glutamate-cysteine ligase (GCL) (Aggarwal et al., 2007a, b; Kunnumakkara et al., 2008). From the above discussions, it is clear that curcumin puts forth its anticancer properties by modulating numerous cellular proteins, signaling pathways, etc., which are summarized in Table 8.1.

Effect of curcumin on normal cells Tumor cells are more sensitive to curcumin action than that of normal cells. Although the exact mechanism of increased curcumin action in cancer cells than in normal cells is

Table 8.1 Molecular targets of curcumin to induce apoptosis and thus treatment of cancer. Upregulation

Downregulation

Disruption of MMP Release of Cytochrome c Activation of caspase 3 Activation of caspase 8 PARP cleavage Release of apoptosis-inducing factor (AIF) mtDNA damage Proapoptotic proteins Bax, AIF Activation of caspase 3-independent apoptosis Nrf2 signaling pathways Reactive oxygen species Release of endonuclease G p53 tumor suppressor gene CDK inhibitors p53-independent G2/M phase arrest

Inhibitors of apoptosis proteins (IAP) JNK signaling pathway Anti-apoptotic proteins Bcl-2, Bcl-xL DNA repair enzymes AP-1and NF-κB signaling pathways Wnt signaling pathways Extracellular signal-regulated kinase Akt pathway Cell-cell adhesion pathway Growth factors and/or their receptors Ubiquitin proteasome system (UPS) Enzymes involved in onset of tumor Cyclin D1 Mammalian target of rapamycin family STAT1 and STAT3

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unknown, there are some characteristic features of cancer cells that make them different from normal cells and curcumin took that opportunity to show its greater cytotoxic action toward cancer cells (Ravindran et al., 2009). First, to meet the demand of rapid growth, cancer cells need more nutrients. As a result, like other nutrients, the cellular uptake of curcumin is also higher in tumor cells than in normal cells (Kunwar et al., 2008). Second, the glutathione levels in tumor cells tend to be lower than normal cells, resulting in decreased deactivation of curcumin and consequently increased sensitivity of tumor cells to curcumin (Syng-ai et al., 2004). Third, compared to tumor cells, most tumor cells express constitutively active NF-κB and mediate their survival while, on the other hand, normal cells contain a more dormant form of NF-κB in the cytoplasm (Shishodia et al., 2005). Curcumin can suppress the survival and proliferation of tumor cells by suppressing NF-κB-regulated gene products and also stimulate apoptosis through the inhibition of AP-1 (Balasubramanian and Eckert, 2007). It’s ability to kill tumor cells and not normal cells makes curcumin an attractive candidate for drug development.

Resistance to conventional chemotherapy The main objective of cancer chemotherapy is to assign tumor cells to apoptosis following exposure to antitumor agents. Although the current chemotherapeutical drugs, for example platinum drugs, are very potent inducers of apoptosis, resistance develops and is implied when tumor cells fail to undergo apoptosis at clinically appropriate drug concentrations (Siddik, 2003). This resistance can be acquired through chronic drug exposure or it can present itself as an intrinsic event (Chan and Fong, 2007). Considering that the cytotoxic outcome of chemotherapy is a complex process, extending from initial drug entry into cells to the final stages of apoptosis, it follows that intracellular events interfering with any stage of this process will inhibit apoptosis and lead to drug resistance. Resistance mechanisms, therefore, arise as a consequence of numerous intracellular changes, including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis, and increased DNA repair (Siddik, 2003). Recently, it has been proposed that in several cancers, including ovarian cancer, a small portion of cancer cells termed as “cancer stem cells” or “cancer stem-like cells” (CSCs) is responsible for the antagonism of the disease, resistance to therapy, self-renewal, and unlimited proliferation (Solomon et al., 2008). Curcumin shows its cytotoxic activity even on cancer stem cells (Kakarala et al., 2010). Because of numerous mechanisms of cell death employed by curcumin, it is possible that cells may not develop resistance to curcumin-induced cell death and it is logical that chemotherapeutic drugs in combination with curcumin may exert enhanced antitumor activity through synergistic action and/or compensation of the adverse effects (Chan and Fong, 2007). It has been found that by using multisteps in various signaling pathways, pretreatment of curcumin can sensitize cancer cells to current chemotherapeutic drugs (Nessa et al., 2012). The combination treatment may also decrease the systemic toxicity caused by chemotherapies or radiotherapies because of the lower doses required (Sarkar et al., 2006).

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Conclusion From the above explanation, it is clear that tumorigenesis is a multistep process that can be activated by any of various environmental carcinogens, inflammatory agents (such as tumor necrosis factor (TNF) and H2O2), and tumor promoters (such as phorbol esters and okadaic acid). These carcinogens are known to modulate the transcription factors (e.g., NF-κB, AP-1, STAT3), antiapoptotic proteins (e.g., AKT, Bcl-2, Bcl-XL), proapoptotic proteins (e.g., caspases, PARP), protein kinases (e.g., IKK, EGFR, HER2, JNK, MAPK), cell cycle proteins (e.g., cyclins, cyclin-dependent kinases), cell adhesion molecules, COX-2, and growth factor signaling pathways (Aggarwal and Shishodia, 2006). Curcumin exerts its antitumor effects by bringing into play numerous cellular proteins. Those in turn affect multiple steps in the pathways leading to tumorigenesis, thus they can kill a wide variety of tumor cell types through diverse mechanisms. Furthermore, its ability to kill tumor cells and not normal cells makes curcumin an attractive candidate for drug development.

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Lu, H.-F., Yang, J.-S., Lai, K.-C., Hsu, S.-C., Hsueh, S.-C., Chen, Y.-L., Chiang, J.-H., Lu, C.-C., Lo, C., Yang, M.-D., 2009. Curcumin-induced DNA damage and inhibited DNA repair genes expressions in mouse–rat hybrid retina ganglion cells (N18). Neurochem. Res. 34 (8), 1491–1497. MacDonald, B.T., Tamai, K., He, X., 2009. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17 (1), 9–26. Mann, B., Gelos, M., Siedow, A., Hanski, M., Gratchev, A., Ilyas, M., Bodmer, W., Moyer, M., Riecken, E., Buhr, H., 1999. Target genes of β-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc. Natl. Acad. Sci. 96 (4), 1603–1608. Melet, A., Song, K., Bucur, O., Jagani, Z., Grassian, A.R., Khosravi-Far, R., 2008. Apoptotic pathways in tumor progression and therapy. Adv. Exp. Med. Biol. 615, 47–79. Morin, P.J., 1999. Beta-catenin signaling and cancer. BioEssays 21 (12), 1021–1030. Nessa, M.U., Beale, P., Chan, C., Yu, J.Q., Huq, F., 2012. Studies on combination of platinum drugs cisplatin and oxaliplatin with phytochemicals anethole and curcumin in ovarian tumour models. Anticancer Res. 32 (11), 4843–4850. Noguchi, K., Kitanaka, C., Yamana, H., Kokubu, A., Mochizuki, T., Kuchino, Y., 1999. Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J. Biol. Chem. 274 (46), 32580–32587. Norbury, C., Nurse, P., 1992. Animal cell cycles and their control. Annu. Rev. Biochem. 61, 441–470. Novak, A., Dedhar, S., 1999. Signaling through β-catenin and Lef/Tcf. Cell. Mol. Life Sci. 56 (5–6), 523–537. Nurse, P., Masui, Y., Hartwell, L., 1998. Understanding the cell cycle: past, present and future. Nat. Med. 4 (10), 1103–1106. Okazaki, Y., Iqbal, M., Okada, S., 2005. Suppressive effects of dietary curcumin on the increased activity of renal ornithine decarboxylase in mice treated with a renal carcinogen, ferric nitrilotriacetate. Biochim. Biophys. Acta 1740 (3), 357–366. Pae, H.-O., Jeong, G.-S., Jeong, S.-O., Kim, H.S., Kim, S.-A., Kim, Y.-C., Yoo, S.-J., Kim, H.-D., Chung, H.-T., 2007. Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells. Exp. Mol. Med. 39 (3), 267–277. Pan, W., Yang, H., Cao, C., Song, X., Wallin, B., Kivlin, R., Lu, S., Hu, G., Di, W., Wan, Y., 2008. AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncol. Rep. 20 (6), 1553–1559. Park, M.-T., Lee, S.-J., 2003. Cell cycle and cancer. J. Biochem. Mol. Biol. 36 (1), 60–65. Park, M.-J., Kim, E.-H., Park, I.-C., Lee, H.-C., Woo, S.-H., Lee, J.-Y., Hong, Y.-J., Rhee, C.H., Choi, S.-H., Shim, B.-S., 2002. Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial (ECV304) cells by up-regulating cyclin-dependent kinase inhibitor, p21WAF1/CIP1, p27KIP1 and p53. Int. J. Oncol. 21 (2), 379. Peters, J.-M., Franke, W., Kleinschmidt, J., 1994. Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. J. Biol. Chem. 269 (10), 7709–7718. Plummer, S.M., Holloway, K.A., Manson, M.M., Munks, R.J., Kaptein, A., Farrow, S., Howells, L., 1999. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene 18 (44), 6013–6020. Rao, C.V., 2007. Regulation of COX and LOX by curcumin. In: The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. Springer, pp. 213–226. Ravindran, J., Prasad, S., Aggarwal Bharat, B., 2009. Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J. 11 (3), 495–510. Rayet, B., Gelinas, C., 1999. Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18 (49), 6938. Reuter, S., Eifes, S., Dicato, M., Aggarwal, B.B., Diederich, M., 2008. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem. Pharmacol. 76 (11), 1340–1351.

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Usefulness of grape seed polyphenols in the prevention of skin cancer: A mini review

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Faizan Kalekhana, Nandakishore Balab, Suresh Raoa, Michael L.J. Paisb, Mohammed Adnanb, Simon Sajana, Manjeshwar Shrinath Baligaa a

MANGALORE I NSTITUTE OF ONCOLOGY, MANGALORE, INDIA b F AT H ER M U L L E R ME DI CA L COLLEGE , MANGALOR E, INDIA

Introduction Skin, which constitutes 15% of the total adult body weight, is the largest organ of the body (Gupta et al., 2016). It is a very important organ and plays a vital role in protecting against external damage from physical, chemical, and biological agents; it also aids in thermoregulation and helps to prevent excessive water loss from the body (Gupta et al., 2016). From a healthcare perspective, skin ailments are one of the most common but neglected human illnesses. The Global Burden of Disease project has shown that “skin diseases continue to be the fourth-leading cause of nonfatal disease burden worldwide and that most ailments are not life threatening” (Seth et al., 2017). However, skin cancers—squamous cell carcinoma (SCC), basel cell carcinoma (BCC) and melanoma (Mel)—are the most common in some populations (Leiter et al., 2014). Global reports suggest that while the incidence rate of melanoma is on the rise, the associated mortality remains stable. The incidence of nonmelanoma skin cancer is more in the white population, with the highest rates being reported from Australia (Apalla et al., 2017). The intrinsic risk factors that contribute toward carcinogenesis include age above 50, gender, race, weakened or suppressed immune system, and inherited syndromes such as Gorlin syndrome, Rombo, Bazex-Dupre-Christol, and epidermolysis bullosa simplex syndromes, xeroderma pigmentosum, albinism, epidermolysis bullosa simplex, dyskeratosis congenita, and multiple self-healing squamous epitheliomata; while the extrinsic factors encompasses chronic exposure to ultraviolet (UV) radiation from the sun, artificial tanning, exposure to arsenic, previous treatment with radiation therapy, infection by Merkel cell polyomavirus (MCV), and or by Human papillomavirus (HPV) (Thompson et al., 2016). For the prevention of skin cancer, emphasis has been placed on improving awareness about the risk factors as well as strategies on minimizing sunlight exposure, wearing longFunctional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00009-0 © 2020 Elsevier Inc. All rights reserved.

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sleeved protective clothing and hats when outdoors, using high SPF creams, and minimizing or avoiding UV tanning devices (Thompson et al., 2016). Additionally, emphasis is also placed on using pharamacological agents that are nontoxic, safe, affordable, and effective (Singh et al., 2014). Such pharmacological agents are termed chemopreventive agents, and preclinical studies have shown that grape seed polyphenols are useful in the prevention of skin cancer.

Grape seed and their polyphenols The grape, scientifically known as Vitis vinifera, is one of the most important fruits globally with immense dietary and medicinal use (Georgiev et al., 2014; Giovinazzo and Grieco, 2015). Grapes are also an important cash crop, as the fruits are used to make wine (Giovinazzo and Grieco, 2015). Historical evidence indicates that grapes were used in prehistoric times in almost all civilizations to prepare wines (Giovinazzo and Grieco, 2015). Today, grape-based wine and beverage industries are major business firms in many countries (Georgiev et al., 2014; Giovinazzo and Grieco, 2015). In addition to wine and juice, grape seeds are also being recognized as an important fertilizer, feed for domesticated animals, and recently as health supplements in some countries (Singleton, 1992; Bartolome et al., 1996; Georgiev et al., 2014; Giovinazzo and Grieco, 2015). Phytochemically, the seeds are a rich source of procyanidins or proanthocyanidins (Fig. 9.1), which are chemically the dimers, trimers, and oligomers of monomeric catechins or epicatechins (Singleton, 1992; Bartolome et al., 1996; Georgiev et al., 2014; Giovinazzo and Grieco, 2015). Scientific experiments have shown that grape seeds possess free radical scavenging, antioxidant, antimutagenic, antiinflammatory, and antimicrobial activities as well as cardioprotective, hepatoprotective, neuroprotective, and anticarcinogenic properties (Nassiri-Asl and Hosseinzadeh, 2009). Studies have also shown that grape seed

FIG. 9.1 Structure of grape seed procyanidins.

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polyphenols are beneficial and possess antibacterial effects on pathogenic bacteria. They also promote surgical wound healing and melasma in humans while promoting hair growth and preventing chemical and UV-induced skin cancer in mice. These aspects are discussed here.

Grape seed polyphenols are effective in prevention of cancer At a global level, skin cancer is the most common cancer and is more frequent in the fairskinned population (Saladi and Persaud, 2005; Einspahr et al., 2003; Kozma and Eide, 2014; Jordan et al., 2014). The three most important types of skin cancer are BCC, SCC, and melanoma while Merkel cell carcinoma and angiosarcoma are the rare types (Saladi and Persaud, 2005; Einspahr et al., 2003). BCC and SCC are also termed keratinocytic or nonmelanoma skin cancers. From an etiological perspective, reports suggest that individuals with familial genetic syndromes are more susceptible to the development of skin cancers and that exposure to ultraviolet radiation (UV) from the sun is the chief etiological factor (Saladi and Persaud, 2005; Einspahr et al., 2003). In addition, constant/chronic exposure to viral infections by the human papilloma virus as well as ionizing radiation, environmental pollutants, chemical carcinogens, and work-related contact with organic solvents and toxic metals have also been shown to trigger carcinogenesis (Saladi and Persaud, 2005). Scientific studies have shown that grape seed extract was effective in inhibiting the 7,12-Dimethylbenz[a]anthracene (DMBA)-induced 12-O-Tetradecanoylphorbol-13acetate (TPA) promoted two-stage skin carcinogenesis in the SENCAR mouse (Zhao et al., 1999) and the CD-1 mice (Bomser et al., 1999). The topical application of grape seed extract resulted in a reduction in tumor incidence, tumor multiplicity, and tumor volume (Zhao et al., 1999; Bomser et al., 1999) and to mediate this effect by reducing the activity of myeloperoxidase (MPO) (Bomser et al., 1999). Recent reports also suggest that the seed gold nanoparticle was effective as a chemopreventive and antioxidant in Swiss albino mice (Nirmala and Narendhirakannan, 2017). Mechanistic studies indicated that the seed gold nanoparticle induced apoptosis by the downregulation of mutant p53, Bcl-2, and pan cytokeratin (Nirmala and Narendhirakannan, 2017). Grape seed extract is also reported to be a competitive inhibitor of ornithine decarboxylase (ODC) activity as well as decreasing TPA-induced PKC activity (Bomser et al., 2000) while also inhibiting the expression of cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and markers of proliferation (proliferating cell nuclear antigen and cyclin D1) in DMBA-initiated/TPA-promoted mouse skin and skin tumors (Meeran et al., 2009). Grape seed extract inhibited the TPA-induced edema, hyperplasia, leukocyte infiltration, myeloperoxidase, COX-2 expression, and PGE (2) production in mouse skin (Meeran et al., 2009). In addition to the topical application, dietary feeding of grape seed extract has also been shown to be effective in preventing DMBA-induced TPA promoted two-stage skin carcinogenesis, delaying the malignant progression of papillomas into carcinomas (Meeran et al., 2009), reducing DMBA-induced inflammatory hyperplasia, and decreasing

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the percentages of mice with mutations in codon 61 of the Ha-ras oncogene (Kowalczyk et al., 2009). From a phytochemical perspective, studies have shown that both topical and dietary administration of grape seed constituents’ resveratrol, catechin, quercetin, and proanthocyanidin B-2-gallate were effective in mitigating DMBA-induced epidermal hyperplasia, proliferation, inflammation, and hydroxylation of 20 -deoxyguanosine of test variables by 40%–70% (Hanausek et al., 2011). When compared to topical application or oral use, the simultaneous dietary and skin application were observed to be better and to reduce the oxidative, inflammatory, and mutations of Ha-ras in codon 61 (Hanausek et al., 2011). In addition to animal studies, experiments with cultured murine keratinocyte cells have shown that grape seed extract scavenges peroxyl and superoxide radicals and protects from hydrogen peroxide-induced DNA damage, thereby suggesting that the free radical scavenging and antiinflammatory properties play a role in the observed protective effects (Kowalczyk et al., 2009). Studies with SCC 12, a cell line developed from squamous cell carcinoma, indicate that the grape seed proanthocyanidin reduced cell proliferation and increased apoptosis and autophagy (Hah et al., 2017). The polyphenols suppressed the expression of matrix metalloproteinase-2/9, thereby resulting in a decrease in the motility and invasiveness (Hah et al., 2017). Studies with cultured melanoma cells, the most aggressive and metastatic of all skin cancers, suggest that grape seed proanthocyanidins reduce the protein expressions of PI3K and p-Akt, inhibit migration by targeting the overexpression of COX-2, and reduce the activation of β-catenin responsible for cell migration (Vaid et al., 2015). Mechanistic studies suggest that treatment with grape seed proanthocyanidins inhibited butaprost (EP2 agonist) or Cay10580 (EP4 agonist)-induced migration of melanoma cells by reducing the expressions of the downstream targets of β-catenin, the MMP-2, MMP-9, and MITF (Vaid et al., 2015). For further substantiation, animal studies have confirmed that feeding grape seed proanthocyanidins inhibited the migration/extravasation of intravenously injected melanoma cells in the lungs of immune-compromised nude mice by reducing the activation of β-catenin and its downstream targets, such as MMPs, in lungs (Vaid et al., 2015). Studies with human epidermoid carcinoma cells (A431) have confirmed that grape seed extract caused a concentration- and time-dependent inhibition of cellular proliferation and induced cell death (Meeran and Katiyar, 2007; Grace Nirmala et al., 2017). Grape seed extract inhibited both the constitutive as well as EGF-induced increase in phosphorylated proteins of the MAPK family with concomitant reactivation of MAP kinase phosphatases by decreasing the levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylation of Akt at ser473 and by mitigating the constitutive activation of NF-kappaB/p65 and inhibiting the expression of COX-2, iNOS, PCNA, cyclin D1, and MMP-9 (Meeran and Katiyar, 2008). Mechanistic studies have shown that grape seed extract caused dose- and time-dependent apoptosis by reducing the mitochondrial membrane potential (Grace Nirmala et al., 2017), increasing the expression of proapoptotic Bax, decreasing the expression of antiapoptotic Bcl-2 and Bcl-xl, loss of the mitochondrial membrane potential, and cleavage of caspase-9, caspase-3, and PARP (Meeran and Katiyar, 2007). Grape seed extract also inhibited cell proliferation by increasing G1-phase arrest and by decreasing cyclin-dependent kinases (Cdk) Cdk2, Cdk4, and Cdk6 and cyclins D1, D2, and E.

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A concomitant increase in the protein expression of cyclin-dependent kinase inhibitors (Cdki), Cip1/p21 and Kip1/p27, and enhanced binding of Cdki-Cdk were also observed (Meeran and Katiyar, 2007). Further, treatment of athymic nude mice with grape seed extracts (50 or 100 mg/kg body weight/mouse) reduced the growth of A431-xenografts in mice by inhibiting the transcription of PCNA and cyclin D1 and reducing the activity of NF-kB (Meeran and Katiyar, 2008).

Grape seed polyphenols are effective in preventing UVinduced skin carcinogenesis Exposure to environmental UVR, a minor component of solar radiation, causes myriad biological effects. However, the manifestation and development of UVR-induced changes are proportional to the exposure time, light intensity, and above all the genetic susceptibility of the individual. Low-level exposure stimulates the formation of vitamin D, which is essential for the absorption of calcium and phosphorous, while high-level exposure causes sunburns. The UVR component of sunlight is probably the most important etiologic agent for the development of many skin disorders, the most important being skin cancer (Kozma and Eide, 2014; Jordan et al., 2014). UVR is a powerful carcinogen and multiple exposures are proved to cause skin cancer by causing mutations (Kozma and Eide, 2014). At doses between these, UV causes gene mutation, suppresses immunity, and promotes inflammation, which lead to mutagenesis and carcinogenesis (Sharma and Katiyar, 2010). With regard to GSP, studies by Mittal et al. (2003) showed that feeding grape seed proanthocyanidins to SKH-1 hairless mice was effective in reducing tumor incidence, tumor multiplicity, and tumor size in the UVB-induced complete (both initiation and promotion), initiation, and promotion stages of photocarcinogenesis. Additionally, studies with extract prepared from red grape seeds (Burgund mare variety) have also shown that its topical application was effective in preventing UVB-induced oxidative stress and mediated this by increasing GSH and glutathione peroxidase levels, by decreasing lipid peroxidation and production of nitric oxide (Filip et al., 2011). Grape seed extract reduced the UVB-induced infiltration of proinflammatory leukocytes and the activities of myeloperoxidase, cyclooxygenase-2 (COX-2), prostaglandin (PG) E(2), cyclin D1, and proliferating cell nuclear antigen (PCNA) in the skin and skin tumors (Sharma and Katiyar, 2010). Subsequent studies have also shown that grape seed proanthocyanidins mediated the protective effects by eliciting multiple pathways such as reducing UVB-induced oxidative damage (Mittal et al., 2003), inhibiting inflammation (Katiyar, 2016; Katiyar et al., 2017), reducing caspase 3 activity (Filip et al., 2011), decreasing skin fat content (Mittal et al., 2003), triggering the rapid repair of damaged DNA, (Katiyar, 2016; Katiyar et al., 2017), stimulating the immune system (Vaid et al., 2010; Katiyar, 2016; Katiyar et al., 2017), stimulating the DNA repair-dependent functional activation of antigen-presenting cells, and stimulating the CD8(+) effector T cells (Vaid et al., 2013; Katiyar, 2016; Katiyar et al., 2017). Grape seed extract decreased the proinflammatory cytokines (TNF-α, IL-1b, and IL-6), increased the

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levels of nucleotide excision repair genes (XPA, XPC, DDB2, and RPA1) in the IL-12 proficient mice (Vaid et al., 2010), increased IL-12 (immunostimulatory cytokine) (Sharma and Katiyar, 2010), and modulated the UVB-induced inflammation and immunosuppression by decreasing IL-10. Studies with human epidermal keratinocytes (NHEK) have shown that the grape seed extract treatment before exposure to UVB was useful in inhibiting hydrogen peroxide (H2O2), lipid peroxidation, protein oxidation, DNA damage, and the depletion of antioxidants (glutathione peroxidase, catalase, superoxide dismutase, and glutathione) (Mantena and Katiyar, 2006). Experiments with NHEK cells also showed that grape seed extract inhibited UVB-induced phosphorylation of ERK1/2, JNK, p38 proteins, and the activation of NF-kappaB/p65 (Mantena and Katiyar, 2006). Additionally, grape seed extract reduced the UVB-induced increase in ROS and NF-kB p65 protein levels and increased apoptosis and Bax-α levels in HaCaT cells (Decean et al., 2016). Together, all these observations indicate the usefulness of grape seed extract as a photoprotective agent with clinical use against UV-induced carcinogenesis.

Conclusion The results accrued from myriad experiments indicate that grape seed extract has the potential to be an effective dermaprotective agent and to mediate these effects by multiple mechanisms (Fig. 9.2). Grape seed extract is shown to be devoid of any toxic effects when

Oxidative stress, Inflammation Metastasis and angiogenesis

Free radical scavenging Phase I and II enzymes

Cancer cell proliferation

Antioxidative enzymes

Mitogenic proliferative signals

Pro apoptotic proteins

Oncogenic transcription factors Cell cycle regulatory proteins

Anti apoptotic proteins Signal transduction molecules

FIG. 9.2 Molecular targets of grape seed polyphenols in the prevention of skin cancer. Symbols depict # ¼ decrease and " ¼ increase.

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administered for a long period of 90 days (Wren et al., 2002), which validates its nontoxic property. In lieu of these observations, it is suggested that translational studies are required to ascertain its beneficial use to humans.

References Apalla, Z., Lallas, A., Sotiriou, E., Lazaridou, E., Ioannides, D., 2017. Epidemiological trends in skin cancer. Dermatol. Pract. Concept. 7, 1–6. Bartolome, B., Hernandez, T., Bengoechea, M.L., Quesada, C., Gomez-Cordoves, C., Estrella, I., 1996. Determination of some structural features of procyanidins and related compounds by photodiodearray detection. J. Chromatogr. A 723, 19–26. Bomser, J.A., Singletary, K.W., Wallig, M.A., Smith, M.A., 1999. Inhibition of TPA-induced tumor promotion in CD-1 mouse epidermis by a polyphenolic fraction from grape seeds. Cancer Lett. 135, 151–157. Bomser, J., Singletary, K., Meline, B., 2000. Inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)induced mouse skin ornithine decarboxylase and protein kinase C by polyphenolics from grapes. Chem. Biol. Interact. 127, 45–59. Decean, H., Fischer-Fodor, E., Tatomir, C., Perde-Schrepler, M., Somfelean, L., Burz, C., Hodor, T., Orasan, R., Virag, P., 2016. Vitis vinifera seeds extract for the modulation of cytosolic factors BAX-α and NF-kB involved in UVB-induced oxidative stress and apoptosis of human skin cells. Clujul Med. 89, 72–81. Einspahr, J.G., Bowden, G.T., Alberts, D.S., 2003. Skin cancer chemoprevention: strategies to save our skin. Recent Results Cancer Res. 163, 151–164. Filip, A., Daicoviciu, D., Clichici, S., Mocan, T., Muresan, A., Postescu, I.D., 2011. Photoprotective effects of 2 natural products on ultraviolet B-induced oxidative stress and apoptosis in SKH-1 mouse skin. J. Med. Food. (Epub ahead of print). Georgiev, V., Ananga, A., Tsolova, V., 2014. Recent advances and uses of grape flavonoids as nutraceuticals. Nutrients 6 (1), 391–415. Giovinazzo, G., Grieco, F., 2015. Functional properties of grape and wine polyphenols. Plant Foods Hum. Nutr. 70 (4), 454–462. Grace Nirmala, J., Evangeline Celsia, S., Swaminathan, A., Narendhirakannan, R.T., Chatterjee, S., 2017. Cytotoxicity and apoptotic cell death induced by Vitis vinifera peel and seed extracts in A431 skin cancer cells. Cytotechnology. https://doi.org/10.1007/s10616-017-0125-0 5 October 2017. Gupta, A.K., Bharadwaj, M., Mehrotra, R., 2016. Skin cancer concerns in people of color: risk factors and prevention. Asian Pac. J. Cancer Prev. 17 (12), 5257–5264. Hah, Y.S., Kim, J.G., Cho, H.Y., Park, J.S., Heo, E.P., Yoon, T.J., 2017. Procyanidins from Vitis vinifera seeds induce apoptotic and autophagic cell death via generation of reactive oxygen species in squamous cell carcinoma cells. Oncol. Lett. 14 (2), 1925–1932. Hanausek, M., Spears, E., Walaszek, Z., Kowalczyk, M.C., Kowalczyk, P., Wendel, C., Slaga, T.J., 2011. Inhibition of murine skin carcinogenesis by freeze-dried grape powder and other grape-derived major antioxidants. Nutr. Cancer 63 (1), 28–38. Jordan, L., Malerich, S., Moon, S., Spencer, J., 2014. Review and assessment of global and domestic ultraviolet light protection programs. J. Drugs Dermatol. 13 (9), 1099–1103. Katiyar, S.K., 2016. Dietary proanthocyanidins inhibit UV radiation-induced skin tumor development through functional activation of the immune system. Mol. Nutr. Food Res. 60 (6), 1374–1382. Katiyar, S.K., Pal, H.C., Prasad, R., 2017. Dietary proanthocyanidins prevent ultraviolet radiation-induced non-melanoma skin cancer through enhanced repair of damaged DNA-dependent activation of immune sensitivity. Semin. Cancer Biol. 46, 138–145.

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Kowalczyk, M.C., Walaszek, Z., Kowalczyk, P., Kinjo, T., Hanausek, M., Slaga, T.J., 2009. Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention. Carcinogenesis 30, 1008–1015. Kozma, B., Eide, M.J., 2014. Photocarcinogenesis: an epidemiologic perspective on ultraviolet light and skin cancer. Dermatol. Clin. 32, 301–313. Leiter, U., Eigentler, T., Garbe, C., 2014. Epidemiology of skin cancer. Adv. Exp. Med. Biol. 810, 120–140. Mantena, S.K., Katiyar, S.K., 2006. Grape seed proanthocyanidins inhibit UV-radiation-induced oxidative stress and activation of MAPK and NF-kappaB signaling in human epidermal keratinocytes. Free Radic. Biol. Med. 40, 1603–1614. Meeran, S.M., Katiyar, S.K., 2007. Grape seed proanthocyanidins promote apoptosis in human epidermoid carcinoma A431 cells through alterations in Cdki-Cdk-cyclin cascade, and caspase-3 activation via loss of mitochondrial membrane potential. Exp. Dermatol. 16, 405–415. Meeran, S.M., Katiyar, S.K., 2008. Proanthocyanidins inhibit mitogenic and survival-signaling in vitro and tumor growth in vivo. Front. Biosci. 13, 887–897. Meeran, S.M., Vaid, M., Punathil, T., Katiyar, S.K., 2009. Dietary grape seed proanthocyanidins inhibit 12-O-tetradecanoyl phorbol-13-acetate-caused skin tumor promotion in 7,12-dimethylbenz[a] anthracene-initiated mouse skin, which is associated with the inhibition of inflammatory responses. Carcinogenesis 30, 520–528. Mittal, A., Elmets, C.A., Katiyar, S.K., 2003. Dietary feeding of proanthocyanidins from grape seeds prevents photocarcinogenesis in SKH-1 hairless mice: relationship to decreased fat and lipid peroxidation. Carcinogenesis 24, 1379–1388. Nassiri-Asl, M., Hosseinzadeh, H., 2009. Review of the pharmacological effects of Vitis vinifera (grape) and its bioactive compounds. Phytother. Res. 23, 1197–1204. Nirmala, J.G., Narendhirakannan, R.T., 2017. Vitis vinifera peel and seed gold nanoparticles exhibit chemopreventive potential, antioxidant activity and induce apoptosis through mutant p53, Bcl-2 and pan cytokeratin down-regulation in experimental animals. Biomed. Pharmacother. 89, 902–917. Saladi, R.N., Persaud, A.N., 2005. The causes of skin cancer: a comprehensive review. Drugs Today 41 (1), 37–53. Seth, D., Cheldize, K., Brown, D., Freeman, E.F., 2017. Global burden of skin disease: inequities and innovations. Curr. Dermatol. Rep. 6 (3), 204–210. Sharma, S.D., Katiyar, S.K., 2010. Dietary grape seed proanthocyanidins inhibit UVB-induced cyclooxygenase-2 expression and other inflammatory mediators in UVB-exposed skin and skin tumors of SKH-1 hairless mice. Pharm. Res. 27, 1092–1102. Singh, M., Suman, S., Shukla, Y., 2014. New enlightenment of skin cancer chemoprevention through phytochemicals: in vitro and in vivo studies and the underlying mechanisms. Biomed. Res. Int. 2014. 243452. https://doi.org/10.1155/2014/243452. Singleton, V.L., 1992. Tannins and the qualities of wines. In: Laks, P.E., Hemingway, R.W. (Eds.), Plant Polyphenols. Plenum Press, New York, pp. 859–880. Thompson, A.K., Kelley, B.F., Prokop, L.J., Murad, M.H., Baum, C.L., 2016. Risk factors for cutaneous squamous cell carcinoma outcomes: a systematic review and meta-analysis. JAMA Dermatol. 152 (4), 419–428. Vaid, M., Sharma, S.D., Katiyar, S.K., 2010. Proanthocyanidins inhibit photocarcinogenesis through enhancement of DNA repair and xeroderma pigmentosum group A-dependent mechanism. Cancer Prev. Res. (Phila.) 3, 1621–1629. Vaid, M., Singh, T., Prasad, R., Elmets, C.A., Xu, H., Katiyar, S.K., 2013. Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice. Cancer Prev. Res. (Phila.) 6 (3), 242–252.

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Vaid, M., Singh, T., Prasad, R., Kappes, J.C., Katiyar, S.K., 2015. Therapeutic intervention of proanthocyanidins on the migration capacity of melanoma cells is mediated through PGE2 receptors and β-catenin signaling molecules. Am. J. Cancer Res. 5 (11), 3325–3338. Wren, A.F., Cleary, M., Frantz, C., Melton, S., Norris, L., 2002. 90-day oral toxicity study of a grape seed extract (IH636) in rats. J. Agric. Food Chem. 50, 2180–2192. Zhao, J., Wang, J., Chen, Y., Agarwal, R., 1999. Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse skin two-stage initiation-promotion protocol and identification of procyanidin B5-30 -gallate as the most effective antioxidant constituent. Carcinogenesis 20, 1737–1745.

10

Indian herbal medicine and their functional components in cancer therapy and prevention Jiwan S. Sidhu, Tasleem A. Zafar DEPARTMENT OF FOOD SCIENCE A ND NUTRITION, COLLEGE OF LI FE SC IENC ES, KUWAI T UN I VE RSIT Y, K UW AI T CIT Y, KU WA I T

Introduction Cancer has been reported as the second leading cause of human death worldwide after cardiovascular diseases (Kaur and Kaur, 2015). Colorectal cancer is the third most common type of cancer and is the second leading cause of cancer-related deaths all over the world (Hemeryck et al., 2016). Although the root causes of cancer occurrence in humans are unclear, diet and nutrition are considered among the leading risk factors. More than 90% of gut-related cancers are associated with diet (Doll and Peto, 1981), and these findings have been supported by extensive epidemiological studies. Many recent studies have shown that various plant food components in our diet might play a major role in delaying or preventing cancer (Li et al., 2016; Tao et al., 2018). Moreover, several plant foods such as fruits, vegetables, mushrooms, herbal tea, spices, whole grains, and legumes, which contain dietary fiber and numerous phytochemicals, play a vital role in reducing the risk of development of various types of cancers (Sidhu et al., 2007; Xu et al., 2016; Seidel et al., 2017). Oxidative stress has been implicated in checking cancer cell growth and behavior. Because of a higher rate of metabolism, cancer cells produce higher amounts of reactive-oxygen species (ROS) than normal cells, thus leading to their oxidative stressinduced apoptosis (Trachootham et al., 2009). Therefore, a number of chemotherapeutic strategies have been formulated to sufficiently raise ROS levels with the objective of causing irreparable damage to cancer cells, eventually leading to the deaths of the tumor cells (Wang and Yi, 2008). This approach has been followed for arresting the growth of cancer cells or eventually causing their death by using various phytochemicals present in plant foods (Nakagawa et al., 2001). Many urban and rural communities still make use of several plant-derived products for the treatment of various diseases, including certain types of cancers. Considering the important role that various phytochemicals in plant foods could play in preventing cancer, Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00010-7 © 2020 Elsevier Inc. All rights reserved.

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a few of the important herbal products, spices, fruits, and vegetables such as turmeric, tamarind, ginger, garlic, onions, Moringa oleifera, neem, Indian gooseberry, beetroot, bitter gourd, and pomegranate will be discussed in this chapter.

Turmeric (Curcuma longa) Phytochemicals present in various fruits, vegetables, and herbs have been shown to provide beneficial effects for human health. By immersing these materials in water, phytochemicals such as naringenin, kaempferol, apigenin, curcumin, chlorogenic acid, gallic acid, hydroxybenzoic acid, β-carotene, lycopene, lutein, theobromine, and zeaxanthin are released into the water, which provides a wide range of benefits in the form of healthy drinks for daily usage (Thiagarajah et al., 2019). Because of scientific advances in identifying these bioactive compounds and their efficacy in the treatment of various diseases, including cancer, many cancer patients have used these to improve their life expectancy as well as reduce the harmful side effects of chemotherapy (Ortega and Campos, 2019).

Bioactive compounds in turmeric Phytochemicals, curcumin, and essential oils present in turmeric that have been shown to prevent cancer have been the subjects of many studies (Srinivasan, 2017; Xiang et al., 2018; Gupta et al., 2017a, b; Jamwal, 2018; Hosseini and Hosseinzadeh, 2018; Amalraj et al., 2017; Benarba and Pandiella, 2018). These studies have suggested that curcuminoids have extensive biological activity with roles as antioxidants, neuroprotectives, antiinflammatories, anticancers, antiacidogenics, radioprotectives, and antiarthritics while offering potential therapeutic roles in colon, lung, and breast cancers as well as inflammatory bowel diseases. A number of curcumin derivatives such as chitin-glucan quercetin conjugate, cyclic peptide conjugate, curcumin mimics, curcumin sulfonamide hybrids, coprecipitate of curcumin/PVP, curcumin-clay hybrids, and curcumin-loaded whey protein microgels have also been prepared that have been indicated to possess anticancer properties (Table 10.1).

Curcumin in cancer prevention Cancer, being a dreadful disease, is a major health-care issue for the human race. Phytochemicals present in many herbs and medicinal plants have been explored for cancer cures as these bioactive substances specifically act on tumor cells (Iqbal et al., 2017). These compounds can block or slow the growth of cancer cells without any side effects on healthy tissues. Curcumin has been shown to modulate epigenetic changes in cancer cells, especially a DNA hypomethylation agent in colon, prostrate, and breast cancer cells. This shows its chemopreventive properties through the modulated expression of oncogenic and tumor-suppressive micro-RNAs (Shanmugam et al., 2019). Srivastava and Srivastava (2019) have illustrated that curcumin and quercetin synergistically inhibit cancer cell proliferation by the downregulation of the Wnt/β-catenin signaling pathway

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Table 10.1 Various curcuminoid-based formulations and their prospective application in different cancer situations. Model used and study design

Effect of curcuminoid treatment

Tf-CUR-SLNPs

MCF-7 breast cancer cells

Mulik et al. (2010)

Anticancer

CUR-PTX administrated in oil-in-water nanoemulsion

SKOV3 tumorbearing nu/nu female mice

Anticancer

CarboxymethylcelluloseTHC conjugates

Human colon adenocarcinoma cell lines (HT-29)

Anticancer

BDMC analog loaded chitosan-starch nanocomposite

MCF-7 breast cancer cell lines and VERO cell lines

Anticancer, antiaging, and anticytotoxic effect Anticancer and anti cytotoxic effect

“Cureit”—a novel bioavailable CUR formulation

Hyaluronidase inhibition assay human vascular endothelial cells

The cytotoxicity, anticancer activity, ROS, and cell uptake were found to be increased considerably with Tf-CUR-SLNPs compared to CUR, CUR-SSS, and CUR-loaded SLNPs These nanoemulsion formulations can serve as an effective delivery carrier for oral administration of anticancer agents High selective cytotoxicity against HT-29. Sustained release in the colon to be an effective treatment for colonic cancer BDMCA-CS showed good drug entrapment efficiency and percentage drug content. In vitro drug release profile showed a very slow, sustained diffusion, controlled release, and polymeric erosion of the drug Inhibit elastase activity at higher concentration. Highest inhibition of 42% to hyaluronidase

CUR-loaded mixed micelles of Pluronic F-127127 and Gelucire 44/14

Human lung cancer cell line A549

UR-MM showed significant improvement in cytotoxic activity as 3-fold and oral bioavailability around 55-fold of CUR as compared to CUR alone

Patil et al. (2015)

Disease

Formulation

Anticancer

Reference

Ganta et al. (2010)

Plyduang et al. (2014)

Subramanian et al. (2014)

Gopi et al. (2014a, b)

Adapted from Amalraj, A., Pius, A., Gopi S., Gopi, S., 2017. Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives. J. Tradit. Complement. Med. 7, 205–213.

proteins (DVL-2, β-catenin, cyclin D1, Cox2, and Axin2) as well as through the downregulation of BCL2 and the induction of caspase 3/7 thru PARP cleavage, thus leading to apoptosis of cancer cells. Suhito et al. (2019) recently developed a rapid and sensitive method for detection of the anticancer effects of curcumin on one of the most aggressive tumors, glioblastoma, in humans. Paclitaxel (PTX) is a commonly used microtubule stabilizing anticancer drug, but has side effects other than having lower brain penetration. Fratantonio et al. (2019) have shown that curcumin in combination with PTX most impressively activated caspase-3, which enhanced the apoptosis of cancer cells; this combination also lowered the expression of the antiapoptotic protein BCL-2.

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Curcumin has also been shown to possess hepatoprotective properties by ReyesGordillo et al. (2017). According to them, curcumin has many beneficial properties such as inhibition of NF-кB activation, prevention of proinflammatory cytokine and interleukin production, enhancing antiinflammatory cytokines, and lowering liver inflammation, thus protecting against hepatocellular carcinoma. Kumari et al. (2018) prepared transferrin-anchored poly(lactide)-based micelles to improve the anticancer activity of curcumin in liver and cervical cancer cells. Curcumin has also been shown to inhibit growth potential by G1 cell cycle arrest and by inducing apoptosis in p53mutated COL320DM human colon adenocarcinoma cells (Dasiram et al., 2017). In another study, Gaikwas et al. (2017) enhanced the in vitro antiangiogenesis activity and cytotoxicity in lung cancer cells by using pectin-PVP-based curcumin particulates, as the dissolution of this conjugate was many times more than the curcumin alone. Interestingly, the use of liposomes loaded with curcumin is a promising intervention for asthma therapy as it suppresses the proinflammatory markers (Ng et al., 2018). Curcumin, a naturally occurring bioactive compound in turmeric, has been known for treating a wide range of diseases in human history. Delivering the active ingredient, curcumin, in the most bioavailable form to the patients is of great importance. Now, a nanotechnological approach has been followed to deliver this bioactive compound to the person for treatment of various diseases. The following options have been reported: curcumin-loaded solid lipid nanoparticles for improved anticancer activity (Rompicharla et al., 2017), novel ultrasound-responsive chitosan/perfluorohexane nanodroplets for image-guided smart delivery of curcumin (Baghbani et al., 2017), curcuminloaded rice bran albumin nanoparticle formulation for increased in vivo bioavailability (Liu et al., 2018a, b), pickering emulsions stabilized nanocellulosic-based nanoparticles for curcumin nanoencapsulations for anticancer and antimicrobial activities (Ngwabebhoh et al., 2018), and bovine serum albumin (BSA)-coated iron oxide magnetic nanoparticles as biocompatible carriers for a curcumin anticancer drug (Nosrati et al., 2018). Curcumin-loaded poly(lactic acid) nanocapsules obtained from pectin-mediated synthesis were found to be more effective in penetrating cancer cells and can cause sustained drug release for effective cancer treatment (Alippilakkottee and Sreejith, 2018). Venkatasubhu and Anusuya (2017) have suggested the use of a cotton cloth coated with a curcumin nanocomposite for wound dressing, as it increases drying time by 74% as well as water absorbency by 50% with higher antibacterial effectiveness against the bacterial species present in the wounds. Curcumin-based nanomedicines have also been reported to reverse cancer drug resistance, rapid internalization and improved anticancer efficacy (Khan et al., 2018). In another recent study, Karimpour et al. (2019) developed curcuminloaded gemini surfactant nanoparticles for improved anticancer activity against breast cancer cell lines. A similar breast cancer therapy for the improved targeted delivery of curcumin via phenylboronic acid-functionalized zinc oxide nanoparticles has been developed by Kundu et al. (2019).

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Ginger (Zingiber officnale Roscoe) Since time immemorial, ginger rhizome has been used as a cooking spice and herbal remedy in many traditional systems of medicine in many Asian countries. Ali et al. (2008) reviewed the phytochemical, pharmacological, and toxicological properties of ginger. According to them, the volatile oil obtained from ginger contains some 50 components, including many terpenoids and pungency principles such as gingerols (phenolics). These compounds are reported to possess immunomodulatory, antitumorigenic, antiinflammatory, antiapoptotic, antilipidemic, antiemetic, and antihyperglycemic properties (Arablou and Aryaeian, 2018; Semwal et al., 2015; Narendra Babu et al., 2018). The phenolics and flavonoids in ginger have been shown to possess the capability to scavenge reactive oxygen species (Aruoma et al., 1997; Surh, 1999; Svarc-Gajic et al., 2017; Okesola et al., 2019).

Anticancer properties Although we still do not know the role of phytochemicals as antioxidants or modulators of other processes related to carcinogenesis or cancer prevention, the consumption of fruits and vegetables containing such antioxidants has been associated with lower rates of cancer (Collins, 1995; Gullett et al., 2010; Da Silva et al., 2012; Vemuri et al., 2017; Haris et al., 2018; Farombi et al., 2019). In an earlier study, diarylheptanoids and gingerol-related bioactives from ginger have been shown to possess cytotoxic and apoptotic activities (Wei et al., 2005). The cancer-preventive properties of ginger rhizome have been reviewed by Shukla and Singh (2007), who listed many other uses of ginger such as aiding in digestion and treating stomach ailments, diarrhea, and nausea. Ginger rhizome was earlier suggested as a promising spice to modify carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in rats (Dias et al., 2006). Recently, Zhang et al. (2016a) investigated edible ginger-derived nanoparticles for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. The use of edible ginger-derived nanolipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy has also been proposed as a promising approach to improve cancer treatment (Zhang et al., 2016b). As inflammatory mediators, leukotrienes play an important role in chronic inflammation-associated carcinogenesis. The use of a new gingerol derivative for creating and docking leukotriene A4 hydrolase as a potential cytotoxic agent for colorectal cancer therapy has been suggested by El-Naggar et al. (2017). Dietary natural compounds such as plant-based phenolic gingerols and gingerol-derived shogaols have been investigated for the prevention and treatment of colon cancer and chronic inflammation by a number of researchers (Tao et al., 2018; Loung et al., 2018). Lua et al. (2015) reported that inhaled ginger aromatherapy has a significant effect in reducing chemotherapy-induced nausea and vomiting and improving the health-related quality of life in women suffering from breast cancer. In another study, [10]-gingerol, a major phenolic in ginger rhizome, has been reported to induce cell cycle arrest and

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apoptosis in triple-negative breast cancer cells. Kapinove et al. (2017) recently reviewed current breast cancer research and suggested that the use of plant-based functional foods is better than the single phytochemical in treating breast cancer because of the synergistic effects of the wide mixture of bioactives present in plant foods. A mixture of green tea and ginger polyphenols has been shown to have apoptotic, cytotoxic, and antioxidant effects in hepatoma cells (Hessien et al., 2013). The anticancer activity of 6-gingerol from the ginger rhizome has been shown to have a synergistic effect with anticancer drugs on human cervical adenocarcinoma cells (Zhang et al., 2017). Recently, the role of a wide variety of natural phytochemicals present in many fruits and vegetables, including ginger, has been reviewed to focus on the mechanism and the prevention and management of lung cancer by Cao et al. (2019).

Tamarind (Tamarindus indica L.) Tamarind bean pulp has been used as a condiment in Indian culinary cooking since time immemorial, and its tangy taste is well accepted by most Indians. Various healing properties of tamarind seeds such as digestive, laxative, expectorant, hypoglycemic, antioxidant, antiatherosclerotic, antimutagenic, antiinflammatory, hypolipidemic, antidiabetic, and carminative have been reported (Hemshekhar et al., 2011. The seeds are known to be a rich source of many polyphenolic bioactive compounds, triterpenes, and polysaccharides, which have healing activities for various human diseases. Consumption of tamarind has been recommended to treat oxidative stress, inflammation, thrombolytic disorders, snake bites, diarrhea, ulcers, microbial infections, obesity, and cancer. Sudjaroen et al. (2005) isolated and elucidated the structure of various phenolic antioxidants from tamarind seeds and pericarp. The seeds were found to be richer (6.54 g/kg) in total phenolic compounds than the pericarp (2.82 g/kg) on a dry basis. Because of the higher content of antioxidant phenolics, they opined that tamarind seeds and pericarp are important sources of cancer chemopreventive natural products. To treat various bone-related pathophysiological diseases such as osteoporosis and bone cancer, a stable but biodegradable material is needed on which bone precursor cells could adhere efficiently. Sanyasi et al. (2014) developed a carboxy methyl tamarind polysaccharide matrix for the adhesion and growth of osteoclast-precursor cells. This material did not possess any cytotoxicity and was found to be compatible with human cells. To act as a carrier for camptothecin, an anticancer drug, xyloglucan nanoaggregates have been developed from tamarind seeds with a size of 60–140 nm, which showed an encapsulation efficiency of 42% ( Jo et al., 2010). Ulcerative colitis (UC) is a chronic gastrointestinal disorder that, if not treated properly, could lead to colon cancer. Periaswamy et al. (2018) used tamarind xyloglucan (TXG) to reduce oxidative stress caused by dextran sodium sulfate (DSS), which was used to create UC in rats. TXG was shown to be a strong antioxidant that could play an important role in reducing UC in mice; this could be tested for extrapolation to human cases. The use of tamarind seeds has also been suggested by Martinello et al. (2017) to have chemopreventive activity against the development of colon carcinogenesis,

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although a hypercholesterolemic diet might reduce this protection. Yeasmin et al. (2017) prepared shape-controlled silver nanoparticles using tamarind seed powder. These nanoparticles of 10–78 nm were found to exhibit dose-responsive antitumor cum antioxidant activity with high selectivity against cervical cancer or lung cancer cell lines; they could find potential use in anticancer therapy.

Onion (Allium cepa L.) and garlic (Allium sativum L.) Onions are a staple in every kitchen all over the world. They are enjoyed for their flavor, but they are also packed with many bioactive organic sulfur compounds that provide many health benefits such as antioxidant and antiinflammatory activity while lowering triglycerides, cholesterol, and blood pressure (Sidhu and Zafar, 2016; Sidhu et al., 2019). One of the flavonoids present in onions, quercetin, has been shown to attenuate atherosclerosis plaque development by suppressing inflammation and apoptosis via ROS-regulated P13K/AKT signaling pathways (Luz et al., 2017). As a natural therapeutic agent, quercetin has recently been shown to reduce and treat endometriosis in mice; a beneficial role for treating endometriosis in humans has been suggested (Park et al., 2019). Onion flavonoids such as quercetin and quercetin glycosides have been shown to possess antioxidant, antidiabetic, and anticancer potential to inhibit selected cancer cell lines (Nile et al., 2018). Myricetin, another flavonoid in onions, has been reported to exhibit osteogenic differentiation of human periodontal ligament stem cells. That leads to stronger tooth holding in sockets and prevents tooth loss, thus offering cell-based therapy in dentistry (Kim et al., 2018). Various flavonoids extracted from onions have been shown to offer effective anticancer therapies against colorectal adenocarcinoma cells (Murayyam et al., 2017). Recently, Ibanez-Redin et al. (2019) developed a novel platform for detecting the pancreatic cancer biomarker, CA19-9, using low-cost, screen-printed interdigitated electrodes that were modified by carbon nanoonions and graphene oxide. These biosensors were able to detect CA19-9 in whole cell lysates of colorectal carcinoma samples. Garlic is a well-known plant throughout the world since ancient times, not only for its use in enhancing the flavor of cooked foods but also for its medicinal value (Srinivasan, 2017). Although garlic has many organosulfur compounds, allicin has attracted the most attention so far. The role of garlic’s chemical constituents in human health has been reviewed in a number of recent publications. A recent comprehensive review on allicin and health (Salehi et al., 2019), human allicin-proteome: S-thioallylation of proteins by the garlic allicin (Gruhlke et al., 2019), garlic and its molecules as medicine (Oosthuizen et al., 2018), garlic for gastrointestinal protection and oxidative stress (Collin-Gonzalez and Santamaria, 2017), anticancer effects on human lung cancer (Kaowinn et al., 2018; Cao et al., 2019), antipancreatic cancer activity (Lee et al., 2019), are some of the studies exploring the potential of garlic as health promoting medicinal food. Diallyl disulfide, one of the principal organosulfur compounds present in garlic, is known for its medicinal value, including anticancer activity. The findings of Saini et al.

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(2017) have proposed that the antiproliferative effect of garlic’s organosulfur compounds is due to the intercellular accumulation of reactive oxygen species, which then leads to apoptosis due to DNA damage-induced G2/M phase arrest evoking mitochondrial apoptosis. Recently, Bhaumik et al. (2019) synthesized a number of allicin analogs, and some of their analogs were shown to be very promising anticancer agents. Consumption of aqueous extracts of garlic and lemon has been shown to reduce the tumor burden through angiogenesis inhibition, induction of apoptosis, and modulation of the immune system (Talib, 2017), but the aged garlic extract (AGE) exhibits stronger anticancer activities (Lv et al., 2019). During tumor development, cell cycle deregulation causing uncontrolled cell proliferation is one of the major changes taking place. Any strategy to arrest this proliferation through induction of apoptosis has been investigated by Choi (2017), who has shown that diallyl trisulfide from garlic induces apoptosis and mitotic arrest in AGS human gastric carcinoma cells through ROS-mediated activation of AMP-activated protein kinase. In another study, Xiao et al. (2018) reported that the garlic-derived compound S-allylmercaptocysteine inhibited hepatocarcinogenesis through targeting the LRP6/ Wnt pathway. The role of garlic in liver disease has recently been reviewed in a book chapter by Zou et al. (2018). With the individual use of curcumin and garlic extracts as well as in combination, and their active compounds in combination with Tamoxifen, Vemuri et al. (2018) reported that natural extracts along with Tamoxifen offer a better alternative in cancer treatment. Similarly, by using garlic, green tea, and turmeric extracts in the form of silver nanoparticles, Selvan et al. (2018) reported that silver nanoparticles using curcumin gave the best antioxidant and cytotoxicity activity rather than using the other two extracts. These vegetables and condiments are shown in Fig. 10.1.

Moringa (Moringa oleifera Lam) Moringa, a native of the Indian subcontinent, is an edible evergreen plant that can grow in a wide range of climatic and soil conditions. It is now growing in many other countries of Africa, Europe, and Asia. Out of 13 cultivars, M. oleifera is the most important plant for its phytochemicals and pharmacological properties related to human health (Ma et al., 2018). Apart from other phytochemicals, the Moringa plant has been valued for its glucosinolates and their derivative compounds that have been found to be active against many diseases, including cancer (Ribaudo et al., 2019). A novel polysaccharide (MOP2) consisting of arabinose (35.8%), glucose (6.67%), and galactose (57.53%), having immunostimulatory and MOP-2 enhanced the proliferation of macrophages and promoted the secretion of ROS, nitric oxide, interleukin-6, as well as tumor necrosis factor-α through the activation of mRNA expressions of iNOS, IL-6 and TNF-α (Dong et al., 2018). Tetteh et al. (2019) evaluated the glucosinolate (GS) content in leaves dried by different drying techniques and recommended that the best retention of GS in the

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(B)

(A)

(D)

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(C)

(E)

FIG. 10.1 (A) Ginger, (B) turmeric, (C) tamarind, (D) onion, and (E) garlic. Photographs source: Prof. Jiwan S. Sidhu.

finished product can be obtained by the sun- and oven-drying techniques, even better than freeze drying. Different parts such as roots, leaves, bark, and drumsticks have enormous properties in nutrition, medicine, or industrial utilization (Liu et al., 2018a, b). They reviewed the nutritional ingredients, bioactive compounds, antioxidant properties, applications, and industrial uses for leaves, seeds, roots, gums, bark, and flowers. In another review, a number of researchers also reviewed the recent trends and prospects of M. oleifera for its medicinal, antimicrobial, and antidiabetic properties as well as its phenolics and flavonoids for antioxidant properties, and as a food fortificant for use in bread, biscuits, yogurt, cheese, and soup (Oyeyinka and Oyeyinka, 2018; Gupta et al., 2018; Lin et al., 2018; Prabakaran et al., 2018; Tshabalala et al., 2019). A novel arabinogalactan (MOP-1) has been isolated from the leaves of M. oleifera by He et al. (2018), who also elucidated its structure (it has arabinose, rhamnose, and galactose in molar ratios of 1:7.32:12.12) and found that the leaves possess tremendous antioxidant activity. Elwan et al. (2018) investigated the ethanolic extracts of Moringa leaves as a protective and therapeutic agent against the damage induced by high acute doses of ionizing radiation. The M. oleifera seeds are known to contain lectins, which are carbohydrate binding proteins with beneficial biological properties including cytotoxicity to B16-F10 melanoma cancer cells (Luz et al., 2017). In a later study, Shu et al. (2018) reported that M. oleifera

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seeds extract residue specifically suppressed metastasis of gastric cancer cells at a lower dosage by upregulating the metastasis suppresser, NDRG1. Tiloke et al. (2019) reviewed the development of gold nanoparticles from M. oleifera for cancer therapy to achieve improved survival rates and better quality of life.

Neem (Azadirachta indica) Neem (Azadirachta indica), a precious medicinal plant having more than 300 phytochemicals, belongs to the family Mahogany. It has been used in India since time memorial to cure various ailments, including cancer (Gupta et al., 2017a, b). In the Swahili language, the neem plant is known as Muarubaini, meaning “treat 40 different diseases” while in Persian, it is called Azad Dirakht, which means “free tree” (Subapriya and Nagini, 2005). Sastry et al. (2006) synthesized amide derivatives of nimbolide, a limonoid naturally obtained from neem leaves (Table 10.2). Three of their synthetic products showed cytotoxic activity against a group of human cancer cell lines. Chen et al. (2018) isolated and characterized four limonoid-type nortriterpenoids from neem seeds. These limonoids were found to possess cytotoxic activity and inhibited human breast cancer cells, cervical cancer cells, the melanoma A375 cell line, and the promyelocytic leukemia HL-60 cell line. Table 10.2

Chemical composition and major bioactive compounds in neem leaves.

Chemical composition (fresh leaves, %) Moisture Ash content Protein Fat% Fiber Carbohydrates Bioactive compounds 3-Acetyl-7-tigloyl-lactone-vilasinin 3-Desacetyl-3-cinnamoyl-azadirachtin 3-Desacetyl-salanin 4α,6α-dihydroxy-A-homo-azadiradione 6-desacetylnimbinene Azadirachtanin Azadirachtanin-A β-sitosterol Hyperoside m-Toluylaldehyde Methyl 14-methylpentadecanoate

9.50  0.24 2.81  0.21 1.58  0.34 2.07  0.35 5.92  0.47 78.12  0.35 Isoazadirolide Nimbaflavone Nimbandiol Nimbinene Nimbolide Quercetin Quercitrin Rutin Vilasanin Lineoleoyl chloride Methyl isoheptadecanoate

Adapted from Madaki, F.M., Kabiru, A.Y., Bakare-Odunola, M.T., Mailafiya, S.C., Hamzah, R.U., Edward, J., 2016. Phytochemical and proximate analyses of methanol leaf extract of neem Azadirachta indica. Eur. J. Med. Plants 15(2), 1–6, Hossain, M.A., Al-Toubi, W.A.S., Weli, A.M., Al-Riyami, Q.A., Al-Sabahi, J.N., 2013. Identification and characterization of chemical compounds in different extracts from leaves of Omani neem. J. Taibah Univ. Sci. 7, 181–188, and Subapriya, R., Nagini, S., 2005. Medicinal properties of neem leaves: a review. Curr. Med. Chem. Anticancer Agents 5(2), 149–156.

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In an earlier study by Kurimoto et al. (2014), triterpenoids from fruits of the neem tree have been isolated and reported to have anticancer properties. Neem limonoids have been shown to attach to oncogenic signaling kinases and transcription factors as well as JAK/STAT signaling pathways, thus having potential chemoprotective therapeutic applications (Nagini, 2014). Recently, Zhu et al. (2018) also isolated a new cytotoxic salannin-class limonoid alkaloid from neem seeds that showed inhibitory activity against the human breast cancer MDA-MB-231 cell line (Fig. 10.2). Cancer has become a major public health problem worldwide. In the traditional system of medicine, a number of herbal treatments have been proposed, where neem components hold a prominent place (Dasgupta et al., 2004; Hao et al., 2014; Patel et al., 2016). Nimbolide has been shown to exhibit anticancer effects on human breast cancer cell lines through both the intrinsic and extrinsic pathways (Elumalai et al., 2012; Pooladanda et al., 2018). Trivedi et al. (2018) have shown that an increase in the alkaline pH (to a pH of 8.6) of the ethanolic extract of neem (dose of 1600 μg/mL) reduced the growth of breast cancer cells. Several research studies have demonstrated the effectiveness of neem extract as a chemopreventive agent in the treatment of oral and forestomach cancers (Balasenthil et al., 1999; Manikandan et al., 2008, 2012). Nimbolide, a triterpenoid obtained from neem, has been shown to exhibit anticancer activity by reducing the CD44 positive cell

Antiinflammatory

Cell migration/ Metastasis

Reduces oxidative stress

Inhibition of cell proliferation

Carcinogen detoxification

Induces apoptosis

Neem Cell cycle alteration

Immunity against tumor

Inhibits angiogenesis

Autophagy, Immune surveillance

FIG. 10.2 Possible anticancer mechanisms of neem bioactives.

DNA repair

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population and by inducing mitochondrial apoptosis in pancreatic cancer cells (Kumar et al., 2018). Ethanolic extract from the neem tree has been shown to cause the deaths of prostate cancer cells by inducing apoptosis in a dose-dependent manner, as evidenced by increased DNA fragmentation and a decrease in cell viability (Kumar et al., 2006). Green nanotechnology is proving to be a boon in anticancer drug delivery systems to treat different types of cancer (Dharmatti et al., 2014). Copper oxide nanoparticles using neem leaves have recently been prepared that inflicted significant ROS generation inside the cancer cells to cause DNA fragmentation, leading to cell death (Rehana et al., 2017; Dey et al., 2019). Silver nanoparticles (green AGNPs) prepared by Kummara et al. (2016) had less toxic effects against human red blood cells, but were able to induce greater selective toxicity in cancer cells than chemical AGNPs. Potara et al. (2015) biosynthesized silver nanoparticles to perform as biogenic SERS-nanotags for studying C26 colon carcinoma cells. They prepared Mycosynthesized silver nanoparticles (MAgNPs) and phytosynthesized silver nanoparticles (PAgNPs) and tested them on the healthy cell lines as well as the C26 murine colon carcinoma cells. They reported that MAgNPs showed lower

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FIG. 10.3 (A) Moringa edible drumsticks, (B) moringa tree (Moringa oleifera) bearing drumsticks, (C) neem tree (Azadirachta indica), and (D) neem tree in bloom. Photographs source: Prof. Jiwan S. Sidhu, KU, and Dr. Sudarshan Chellan, KISR.

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cytotoxicity in both the healthy cells and colon carcinoma cells than the PAgNPs. These herbal plants are shown in Fig. 10.3.

Pomegranate (Punica granatum) After cardiovascular diseases, cancer is the second-leading cause of death worldwide. A number of foods of plant origin such as fruits, vegetables, whole grains, beans, herbal tea, and mushrooms have been shown to offer protection against cancer (Tao et al., 2018). Pomegranate has been valued as the best source of phenolic compounds in the human diet since ancient times, mainly because of the biological effects it exerts through the free radical scavenging capabilities (Sidhu and Zafar, 2018). Pomegranate is one such fruit rich in many bioactive compounds that offer health benefits such as antioxidant, antimicrobial, antihelminthic, anticarcinogenic, and immune-boosting properties. Ambigaipalan et al. (2017) isolated and characterized phenolics from pomegranate juice (PJ) as well as seeds (PS) using HPLC-DAD-ESI-MS. According to them, the PJ and PS had phenolic acids (13), monomeric flavonoids (8), hydrolysable tannins (12), proanthocyanidin (1), and anthocyanins (12). These bioactive compounds inhibited DNA damage (induced by free radicals) and copper-induced LDL-cholesterol oxidation. They also observed the presence of α-glucosidase and lipase activities in PJ and PS. Pomegranate fruit shows antioxidant, antiinflammatory, antiangiogenesis, antiproliferative, antimetastatic, antiinvasive, and apoptotic properties. Thus, the consumption of this fruit would assist in leading a healthy life protected from cancers (Khwairakpam et al., 2018). Pomegranate is widely consumed because of its excellent taste and rich content of punicalagin and ellagitannins, and its consumption has been reported to protect against lung cancer (Cao et al., 2019). The intake of pomegranate has also been associated with a reduction of incidences of human papillary thyroid carcinoma BCPAP cells via the NF-кB signaling pathway (Cheng et al., 2018); growth inhibition and apoptosis in human PC-3 and LNCaP prostrate cells (Adaramoye et al., 2017; Deng et al., 2017); and suppression of colon cancer through downregulation of Wnt/β-Catenin in a rat model (Ahmed et al., 2017; Nunez-Sanchez et al., 2017). Now, the application of nanotechnology using pomegranate fruit offers newer possibilities for drug delivery systems such as nanoemulsions, nanoparticles, nanoliposomes, phytosomes, nanovesicles, and niosomes to treat various human ailments, including cancer (Karimi et al., 2017). Sahin et al. (2017, 2018) have shown that AgNPs prepared with pomegranate extract inhibited the proliferation of the human breast cancer cell line MCF-7 and proposed that it may exert its proliferative effect by reducing the DNA synthesis and apoptosis-inducing cell cycle stages.

Amla (Phyllanthus emblica L.) In most countries of Asia and Africa, several herbal plants have been used to treat various ailments, including cancer, since ancient times. Interestingly, half the percentage of modern drugs have been derived from different forms of natural phytochemicals present in the

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plant kingdom (Yadav et al., 2018). Amla has been used in India for many centuries and the usefulness of its fruit, leaves, bark, and roots has been well documented for its medicinal value (Pammei et al., 2019). The fruit is not only the richest source of ascorbic acid, but also an excellent source of pectin, many minerals, and phenolic antioxidants (Alkndari et al., 2019a, b). Amla fruit possesses many health-promoting properties such as anticancer, antioxidant, antiinflammatory, antimicrobial, immunomodulator, and cytoprotective properties. Two new triterpenoids from the roots of Phyllanthus emblica have recently been isolated and characterized by Nguyen et al. (2018). They reported that these bioactive compounds possessed moderate cytotoxicity against the K562 and HepG2 cancer cell lines. Various plant-derived immunomodulators have been extensively discussed in a recently published book chapter by Nair et al. (2018). The reader is also directed to read more about the chemical composition and medicinal value of amla fruit in earlier published book chapters (Sidhu and Zafar, 2012, 2018).

Sugar beet (Beta vulgaris) Sugar beet, also known as table beet, has been a functional food for centuries, and is a traditional and very popular food in many national dishes worldwide. Beet is known to be a rich source of several bioactive compounds such as betaine, betacyanins, betanins, vulgaxanthine, betaxanthins, polyphenols, flavonoids, many vitamins (thiamine, riboflavin, folic acid, biotin, pyridoxine, ascorbic acid), pectin, soluble fiber, and many minerals. All these bioactives are known to offer protection against cancer as well as delay the metastasis (Blazovics and Sardi, 2018). Beetroot has been a part of the Western diet for ages. The betalains present in these vegetable roots have been shown to increase the cytotoxicity in CaCo-2 cancer cells (Farabegoli et al. (2017). Cytotoxicty was mediated by the intrinsic apoptotic pathway with a parallel decrease in antiapoptotic protein B-cell leukemia/lymphoma 2 levels. The anthocyanins present in beetroot also reduced the oxidative stress triggered by hydrogen peroxide in CaCo-2 cells. The antiinflammatory action by betalains was shown by decreasing cyclooxygenase-2 and interleukin-8 mRNA expression after lipopolysaccharide induction in CaCo-2 cells, thus showing its potential as a chemopreventive tool against colon cancer. Beetroot consumption has been suggested by Kapadia et al. (1996) as the most useful means of preventing skin and lung cancers, as they investigated the inhibitory effect of betalains on Epstein-Barr virus early antigen (EBVEA) induction using Raji cells. Venugopal et al. (2017) used beetroot extract for synthesizing silver nanoparticles (AgNPs) for use against human breast (MCF-7), lung (A549), and pharynx (Hep-2) cancer cell lines. These biosynthesized AgNPs showed a better cytotoxic effect against these three cell lines compared to normal cell lines. The mechanism of cell death induced by nanoparticles was due to apoptosis in cancer cells. These vegetables and fruits are shown in Fig. 10.4.

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FIG. 10.4 (A) Bitter gourd, (B) beet root, (C) amla (Indian gooseberry), and (D) pomegranate. Photographs source: Prof. Jiwan S. Sidhu.

Bitter gourd (Momordica charantia) Bitter gourd or bitter melon is a widely distributed vegetable in Asia, Africa, and some South American countries. Though bitter, it is a very common and popular vegetable in Asian countries simply because of its rich taste and nutritional value. This vegetable has been valued for its antidiabetic, anti-HIV, antioxidant, anticancer, antibacterial, immunomodulatory, antiobesity, and antiinflammatory properties. Fang et al. (2012) isolated a MAP30 protein from bitter gourd seeds that promotes apoptosis in liver cancer cells in vitro and in vivo. According to their proposed mechanism of its anticancer properties, this protein contributes both caspase-8 regulated extrinsic and caspase-9 regulated intrinsic caspase-cascades in MAP30-induced cell apoptosis. As bitter gourd is a common vegetable in many Asian countries, MAP30 could serve as a safe agent for the treatment of liver cancer. The bitter gourd plant extract inhibits the growth of cancer cells by inducing apoptosis, autophagy, and cell cycle arrest while inhibiting cancer stem cells (Dandawate et al., 2016). According to their extensive review, the bitter gourd plant is of great medicinal

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valu as it is rich in many bioactive compounds such as cucurbitane-type triterpenoids, linolenic acid, protease inhibitors, and ribonucleases, which inhibit cancer stem cells. Bitter gourd seed oil has been reported to be rich (a 60% level) in conjugated linolenic acid (CLA), which induces apoptosis and was found to upregulate the GADD45, p53, and PPARγ in human colon cancer CaCo-2 cells in a dose-dependent manner (Yasui et al., 2005). The expression level of an apoptosis suppressor Bcl-2 protein decreased, but GADD45 and p53, which have vital roles in apoptosis-inducing pathways, were significantly upregulated by the bitter gourd seed oil. Raina et al. (2016) recently reviewed the role of bioactives present in bitter gourd not only in cancer prevention and therapy, but also in treating obesity and drug-drug interactions due to the effect of the bitter gourd on metabolic enzymes and transporters. This is more important because many individuals are eating bitter gourd to derive health benefits from this vegetable, but at the same time are taking other anticancer allopathic drugs. In a recent review, Farooqi et al. (2018) showed some light on the bioactives isolated from bitter gourd that effectively inhibited cancer development and progression in humans through the regulation of the protein network in cancer cells. They also emphasized the need for more research that can prove useful in getting us closer to personalized medicine one day.

Future research needed Cancer is a disease that develops slowly over a few decades because of very complex interactions between multiple genes within a cell and its neighboring tissues. This gradually turns healthy cells into cancerous cells, leading to the stage of metastasis where other organs may also be affected. The etiology of this disease is very complex, and the various factors involved in the initiation and development of cancer are not clear yet. A small percentage is attributed to gene mutation (due to DNA damage) but a large percentage of cancers are attributed to lifestyle factors (such as dietary factors) and exposure to environmental carcinogens. Radiation and chemotherapy approaches may not be enough to tackle this disease, and more intensive research efforts are needed to elucidate the role of various bioactive compounds present in different foods of plant origin. Consumption of plant-based diets can play a very important role in preventing and treating this disease. More research needs to be undertaken to investigate the mechanism underlying the mode of action of these bioactives in the treatment and prevention of various types of cancers in humans. Recent advances in nanotechnology hold a great future in designing better drug delivery systems for the effective control of various types of cancers. The use of gold, silver, copper, and platinum nanoparticles with optimized shape and size—and based on green technology using various phytochemicals—needs further investigation to enhance the benefits of these noble nanoparticles. More importantly, more research is needed to carry out in vivo trials with these nanoparticles with the objective of finding their role and mechanism inside the human body as anticancer treatments.

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Tshabalala, T., Ndhlala, A.R., Ncube, B., Abdelgadir, H.A., Staden, J.V., 2019. Potential substitution of the root with the leaf in the use of Moringa oleifera for antimicrobial, antidiabetic and antioxidant properties. S. Afr. J. Bot. https://doi.org/10.1016/j.sajb.2019.01.029. Vemuri, S.K., Banala, R.R., Subbaiah, G.P.V., Srivastava, S.K., Reddy, A.V.G., Malarvili, T., 2017. Anti-cancer potential of a mix of natural extracts of turmeric, ginger and garlic: a cell-based study. Egypt. J. Basic Appl. Sci. 4, 332–344. Vemuri, S.K., Reddy, R.B., Subbaiah, G.P.V., Reddy, G.A.V., 2018. Apoptotic efficiency of aqueous extracts of turmeric, garlic and their active compounds in combination with Tamoxifen in lung cancer and oral cancers: a comparative study. Ben-Suef Univ. J. Basic Appl. Sci. 7, 184–197. Venkatasubhu, G.D., Anusuya, T., 2017. Investigation on Curcumin nanocomposite for wound dressing. Int. J. Biol. Macromol. 98, 366–378. Venugopal, K., Ahmed, H., Manikandan, E., et al., 2017. The impact of anticancer activity upon Beta vulgaris extract mediated biosynthesized silver nanoparticles (AgNPs) against human breast (MCF-7), lung (A549) and pharynx (Hep-2) cancer cell lines. J. Photochem. Photobiol. B Biol. 173, 99–107. Wang, J., Yi, J., 2008. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol. Ther. 7 (12), 1875–1884. Wei, Q.Y., Ma, J.P., Cai, Y.J., Yang, L., Liu, Z.L., 2005. Cytotoxic and apoptotic activities of diarylheptanoids and gingerol-related compounds from the rhizome of Chinese ginger. J. Ethnopharmacol. 102, 177–184. Xiang, H., Zhang, L., Xi, L., et al., 2018. Phytochemical profiles and bioactivities of essential oils extracted from seven Curcuma herbs. Ind. Crop. Prod. 111, 298–305. Xiao, J., Xing, F., Liu, Y., 2018. Garlic-derived compound S-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway. Acta Pharm. Sin. B 8 (4), 575–586. Xu, D.P., Zheng, J., Zhou, Y., Li, Y., Li, S., Li, H.B., 2016. Extraction of natural antioxidants from the Thelephora ganbajun mushroom by an ultrasound-assisted extraction technique and evaluation of antiproliferative activity of the extract against human cancer cells. Int. J. Mol. Sci. 171664. Yadav, S.S., Singh, M.K., Singh, P.K., Kumar, V., 2018. Traditional knowledge to clinical trials: a review on therapeutic actions of Emblica officinalis. Biomed. Pharmacother. 93, 1292–1302. Yasui, Y., Hosokawa, M., Sahara, T., … Miyashita, K., 2005. Bitter gourd seed fatty acid rich in 9c,11t, 13tconjugaed linolenic acid induces apoptosis and up-regulates the GADD45, p53, and PPARγ in human colon cancer Caco-2 cells. Prostaglandins Leukot. Essent. Fatty Acids 73, 113–119. Yeasmin, S., Datta, H.K., Chaudhuri, S., Malik, D., Bandopadhyay, A., 2017. In-vitro anti-cancer activity of shape-controlled silver nanoparticles (AgNPs) in various organ specific cell lines. J. Mol. Liq. 242, 757–766. Zhang, M., Viennois, E., Prasad, M., et al., 2016a. Edible ginger-derived nanoparticles: a novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. Biomaterials 101, 321–340. Zhang, M., Xiao, B., Wang, H., et al., 2016b. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Mol. Ther. 24 (10), 1783–1796. Zhang, F., Zhang, J.G., Qu, J., Zhang, Q., Prasad, C., Wei, Z.J., 2017. Assessment of anti-cancerous potential of 6-gingerol (Tongling white ginger) and its synergy with drugs on human cervical adenocarcinoma cells. Food Chem. Toxicol. 109, 910–922. Zhu, J., Lu, X., Fan, X., et al., 2018. A new cytotoxic salanin-class limonoid alkaloid from seeds of Azadirachta indica A. Juss. Chin. Chem. Lett. 29, 1261–1263. Zou, L., Zhang, R., Gao, H., Xiao, J., Tipoe, G.L., 2018. Garlic and liver disease. In: Patel, V., Rajendram, R. (Eds.), The Liver: Oxidative Stress and Dietary Antioxidants, first ed. Academic Press, New York, pp. 337–347.

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Further reading Banuppriya, G., Sribalan, R., Padmini, V., 2018. Synthesis and characterization of curcumin-sulfonamide hybrids: biological evaluation and molecular docking studies. J. Mol. Struct. 1155, 90–100. Bernard, M.M., McConnery, J.R., Hoskin, D.W., 2017. [10]-Gingerol, a major phenolic constituent of ginger root, induces cell cycle arrest and apoptosis in triple-negative breast cancer cells. Exp. Mol. Pathol. 102, 370–376. Darwish, S., Mozaffari, S., Parang, K., Tiwari, R., 2017. Cyclic peptide conjugate of curcumin and doxorubicin as an anticancer agent. Tet. Lett. 58, 4617–4622. Goncalves, J.L.S., Valandro, S.R., Poli, A.L., Schmitt, C.C., 2017. Influence of clay minerals on curcumin properties: stability and singlet oxygen generation. J. Mol. Struct. 1143, 1–7. Hossain, M.A., Al-Toubi, W.A.S., Weli, A.M., Al-Riyami, Q.A., Al-Sabahi, J.N., 2013. Identification and characterization of chemical compounds in different extracts from leaves of Omani neem. J. Taibah Univ. Sci. 7, 181–188. Khwaja, S., Fatima, K., Hasanain, M., et al., 2018. Antiproliferative efficiency of curcumin mimics through microtubule destabilization. Eur. J. Med. Chem. 151, 51–61. Li, X.L., Zhao, C.H., Yao, X.L., Zhang, H., 2017. Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated P13K/AKT signaling pathway. Biomed. Pharmacother. 85, 659–671. Madaki, F.M., Kabiru, A.Y., Bakare-Odunola, M.T., Mailafiya, S.C., Hamzah, R.U., Edward, J., 2016. Phytochemical and proximate analyses of methanol leaf extract of neem Azadirachta indica. Eur. J. Med. Plants 15 (2), 1–6. Matos, R.L., Lu, T., Prosapio, V., et al., 2019. Coprecipitation of curcumin/PVP with enhanced dissolution properties by the supercritical antisolvent process. J. CO2 Util. 30, 48–62. Mohammadian, M., Salami, M., Momen, S., Alavi, F., Emam-Djomeh, Z., 2019. Fabrication of curcuminloaded whey protein microgels: structural properties, antioxidant activity, and in vitro release behavior. LWT-Food Sci. Technol. 103, 94–100. Singh, A., Lavkush, F., Kureel, A.K., Dutta, P.K., Kumar, S., 2018. Curcumin loaded chitin-glucan quercetin conjugate: synthesis, characterization, antioxidant, in vitro release study, and anticancer activity. Int. J. Biol. Macromol. 110, 234–244.

11

Antioxidant phytochemicals in cancer prevention and therapy—An update Abraham Wall-Medranoa, Francisco J. Olivas-Aguirreb a  ´ NOMA DE CIUDAD JUA ´ REZ , INST IT UT O DE CI ENCI AS BIOM EDICAS, U NI VERSIDAD AUTO C I U D AD JU A´ RE Z, MEXICO b DEPARTAMENTO DE CIENCIAS DE LA SALUD, UNIVERSIDAD DE  IC O ´ N, M EX S O N OR A (C AMP U S CA J E M E ) , CI U D AD O B R E G O

Introduction From Leonor Michaelis’ pioneering commentary in 1939 that free radicals, to a certain extent, arise as intermediate products in reversible oxidation systems, a plethora of evidence has documented the action of free radicals in several noncommunicable chronic diseases (NCCD) including diabetes, neurological diseases, and cancer (Phaniendra et al., 2015; Forman et al., 2014). This evidence supports a direct relationship between free radicals and the risk for prodromal hypermetabolic states (e.g., inflammation and obe€ rgyi, the discovsity), most of them associated with unhealthy lifestyles. Albert Szent-Gyo erer of hexurinoc acid (a.k.a vitamin C) in 1927, postulated that an incorrect free radical formation or elimination is the ultimate cause of cancer (Moss, 1988), establishing the basis for intensive research on the bioactivity of free radicals in the early carcinogenicto-metastasis process. Reactive oxygen species (ROS) such as superoxide (O 2 ), hydroperoxide (ROOH), hydroxyl (•OH) radicals, hydrogen peroxide (H2O2), nitric oxide (NO), and other less-reactive prooxidants cause oxidative stress and the instability of proteins, lipids, nucleic acids, and other biomolecules (Phaniendra et al., 2015; Schieber and Chandel, 2014); paradoxically, they are also involved in intracellular signaling, proliferation, and survival in normal and cancer cells. The scientific interest in finding new and better sources of antioxidant phytochemicals (APH) has increased considerably in recent years (Carlsen et al., 2010). Due to this, a growing body of evidence demonstrates that the biological activity of certain APHs extends beyond their antioxidant capacity, including other bioactivities such as enzyme inhibitors, signaling molecules, epigenetic factors, and regulators of many other cellular reactions (Ray et al., 2012). In this sense, alternative and complementary medicine (ACM) is becoming more popular among cancer patients, as is the number of physicians who prescribe nutraceuticals ( John et al., 2016). APHs such as vitamin A, carotenoids, ascorbate, and Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00011-9 © 2020 Elsevier Inc. All rights reserved.

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dehydroascorbate (DHA), D (secosteroids), E (tocols), and phenolic compounds (PCs) can be used as coadjutants to minimize the side effects of conventional cancer therapy (Thyagarajan and Sahu, 2018; Davis et al., 2012). However, the efficacy of these APHs remains debatable. The effective anticancer half maximal effective concentration (EC50) of APHs is conditioned, among other factors, by their chemical diversity and quantity in plant sources (Carlsen et al., 2010) and their bioavailability and first-pass biotransformation within the gastrointestinal (GI) tract (Dominguez-Avila et al., 2017). Such factors may explain the lack of effectiveness of certain APHs for certain types of cancer. As if this were not enough, under certain circumstances, € ber et al., 2016). This chapter presents an certain APHs may become proantioxidants (Gro update on the effectiveness of APHs for primary and secondary prevention of cancer, their molecular mechanisms, natural sources, and the physiological obstacles related to their effectiveness. The new paradigm about the prooxidant action of certain APHs is discussed shortly.

Cancer: Public health burden and ACM Cancer is a multifactorial genetic NCCD considered a global public health problem; it is the second-leading cause of death with probably the highest cost to health systems. Even when it’s cumulative incidence is lower than that of other NCCDs, 17.5 MM cases and 8.7 deaths occurred in 2015 and its 10-year incidence increased by 33% (Fitzmaurice et al., 2017). According to the Global Cancer Observatory (GLOBOCAN), 18.1 MM new cancer cases and 9.6 MM cancer deaths occurred in 2018, with lung and breast (11.6%), prostate, (7.1%), and colorectal (6.1%) cancer the most commonly diagnosed (Bray et al., 2018). This report also indicated that one-fifth of men or one-sixth of women will develop cancer during their lifetime. Public efforts aimed to reduce this burden are yet to be seen, but public health systems should be prepared for an unprecedented growth of cancer cases in the following decade, particularly in low-to-middle income countries. Novel oncological therapies (surgery, radiation, and drugs) are improving the survival rate of cancer patients. However, these interventions often result in metabolic imbalances and secondary illnesses such as malnutrition, inflammatory states, and systemic oxidative stress. That is the reason why patients increasingly seek ACM therapies to deal with cancer treatment side effects. For example, they commonly include protein supplements to mitigate cancer cachexia syndrome, 64%–81% of cancer patients take vitamin and mineral supplements, and 14%–32% begin using them after they are diagnosed (Velicer and Ulrich, 2008). In fact, cancer survivors are common users of vitamins/mineral supplements (+14%) and natural products (+5%) when compared to cancer-free adults (P < 0.001), with both consumer segments spending around $5.2–6.7 billion on vitamin/mineral supplements and other ACM measures ( John et al., 2016). Lastly, most if not all types of cancers are related to systemic oxidative stress (Ozben, 2015; Tong et al., 2015), as will be further discussed. This single fact has directly or indirectly pushed the market of APH-based supplements based on the fact that vitamin

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C> PCs > vitamin E (tocopherols+ tocotrienols) > carotenoids are increasingly being used to produce nutraceuticals, and this trend seems to be unstoppable (Grand View Research, 2016). In fact, 30%–90% of cancer patients use supplements based on APH and immunomodulatory micronutrients (e.g., vitamins C and D, selenium), often without a medical € ber et al., 2016; Davis et al., 2012). It is noteworthy that, at least for prescription (Gro PCs, clinical trials testing the role of APHs as tumor growth inhibitors are very scarce and most of them show conflicting results (Anantharaju et al., 2016), although their recommendations as coadjutants in cancer treatment have been established (Miller and Snyder, 2012; WCRF/AICR, 2007)

Cancer and oxidative stress Oxidative stress should be understood as the imbalanced production of oxidant species (high) and antioxidant (low) species. This tight balance defines the genomic integrity, internal-external signaling, immunity, and integrative metabolism of normal and cancer cells (Thyagarajan and Sahu, 2018). Most ROS come from the respiratory chain (complexes I and III) but environmental stressors such as hypoxia and UV/ionizing radiation also induce cellular ROS production (Tong et al., 2015). Under normal circumstances, ROS regulate important signaling pathways such as phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and the redox factor-1 (Ref1)/transcription factor NFE2-related factor 2 (Nrf2) signaling pathways (Schieber and Chandel, 2014; Ray et al., 2012). Reactive nitrogen species (RNS) crosstalk with ROS to perform specific protein modifications (e.g., nitrosation, nitrosylation), switching inactive-to-active molecular participants in MAPK/PI3K/phosphatase and tensin homolog (PTEN), and nuclear factor-κΒ (NF-κB)/NF-κB inhibitor α (IκB) and Nrf2/Kelch-like ECH-associated protein 1 (KEAP1) pathways (Moldogazieva et al., 2018). The effects of ROS and RNS in such pathways affect cell proliferation, metabolism, redox status, differentiation, and survival of normal cells (Ray et al., 2012). Human cells also have a well-orchestrated antioxidant apparatus to counteract internal oxidative stressors that are complemented with an external protective core of antioxidant molecules of internal (e.g., glutathione) and external (e.g., vitamin C) origin. Cells are protected from ROS initially by the radical scavenging capacity (RSC) of vitamins C and E interfering with sequential oxidative reactions on lipid bilayers (Stevens et al., 2018; Traber and Stevens, 2011). It is noteworthy that the term “antioxidation” traditionally implies a one-electron transfer reaction with free radicals in vitro, but this has been challenged more recently by the nucleophilic tone and para-hormesis theories. These theories indicate that in vivo, such an electronic transfer actually occurs as a two-electron transfer that includes the enzymatic removal of nonradical electrophiles as well (Forman et al., 2014). Excellent review articles have been published on cellular antioxidant systems and redox homeostasis by Proprac et al. (2017), Marengo et al. (2016), and Yang and Lee (2015). A cancer cell uses normal cell machinery to sustain its abnormal growth and proliferation by activating growth factor-mediated pathways and sequestering nutrients from

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normal cells (Schieber and Chandel, 2014). Cancer brings together several malignant neoplasms of epithelial, mesenchymal, or hematological origin whose molecular nature and metabolic activity are different from each other, and some of them are more aggressive than others. Of all cancers, 90% are linked to somatic mutations and environmental factors (including diet) while only 10% are caused by germline mutations. Nevertheless, all cancers are characterized by a rapid multiplication of mutated cells that spreads out their usual limits, invading adjacent or distant normal tissues. The hallmarks of cancer comprise six biological capabilities during its development and progression: (A) sustained antiproliferative signaling, (B) evasion of growth suppressors, (C) invasion and metastasis activation, (D) enhanced replicative immortality, (E) angiogenesis, and (F) resistance to cell death (Hanahan and Weinberg, 2011). Additionally, genomic instability and inflammation foster other metabolic rearrangements required for cancer progression and establishment (Alam et al., 2018). Comprehensive metabolic maps depicting cancer stages, molecular actors, and signaling pathways have helped to discover novel therapeutic targets, including those associated with oxidative stress. For instance, colorectal cancer pathogenesis involves the activation of the Wnt/EGF/EGFR signaling pathway, loss of P53 function, epithelial-mesenchymal transition (MET)/matrix metalloproteinases (MMPs)/intercellular adhesion molecules (ICAMs), and the response of transforming growth factor beta (TGF-β) (Alam et al., 2018; Slaby et al., 2009). Oxidative stress is intrinsically related to all these stages. Cancer cells undergo oxidative stress to a much higher extent than normal cells due to oncogene-induced transformation, higher metabolic activity, mitochondrial dysfunction, and a much higher generation of ROS from mitochondria, endoplasmic reticulum, and NADPH oxidases (Ozben, 2015). ROS preserve mitogenic signals by serving as an "energetic thrifty" switch when highly proliferative tumors outstrip their blood nutrient supply (Schieber and Chandel, 2014; Gatenby and Gillies, 2004). They have also been associated with autophagy, apoptosis, and the cellular immune response of cancer cells (Tong et al., 2015); fortunately, several molecular participants in cancer are targets for APH at many “omic” levels. Nrf2/Keap1. The molecular basis of the aforementioned “oxidative fine-tuning” in normal and cancer cells extends beyond the purpose of this chapter. However, Nrf2/Keap1 deserves special mention as a major antioxidative stress-protecting mechanism, xenobiotic toxicity and inflammation (Pall and Levine, 2015; No et al., 2014). Normally, Nrf2 is targeted by KEAP1 for proteasomal degradation, but this complex is tightly regulated by intracellular ROS levels (Schieber and Chandel, 2014). Under oxidative conditions, nuclear translocation of Nrf2 occurs where it is heterodimerized with small Maf proteins that bind to the antioxidant-responsive elements (AREs) of multiple genes encoding phase II detoxifying enzymes and phase III xenobiotic transport (Bellezza et al., 2018). However, Nrf2 activation in many cases is not enough to reduce inflammation and oxidative stress, so nonenzymatic antioxidants must also be elevated (Prasad, 2016). In this sense, many but not all PCs, carotenoids (lycopene being the most active), and tocols (α-tocopherol being the less active) increase Nrf2 activity (Pall and Levine, 2015). A higher intake of tocols does not suppress Nrf2 signaling nor weaken the endogenous

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antioxidant system in rat liver cells (Eder et al., 2017). On the other hand, Nrf2 hyperactivation leads to reductive stress (Bellezza et al., 2018) and its overexpression protects cancer cells from anticancer agents, thus contributing to chemoresistance (No et al., 2014) while its inhibition (e.g., by siRNA transfection or upregulation of KEAP1) increases cancer cell sensitivity to chemotherapeutic agents (Mostafavi-Pour et al., 2017; Tong et al., 2015). Whether Nrf2/Keap1 action is reduced or amplified by APH during the late stages of carcinogenesis will be discussed in the next sections.

Antioxidant phytochemicals (APH) Edible fruits and vegetables (F&V) are sources of different APHs (type and amount) with varied antioxidant capacity. Carlsen et al. (2010) published the antioxidant nature of >3000 foods consumed worldwide, demonstrating that plant-based foods contribute 8–9 times more antioxidant capacity to the human diet than animal-based foods (median 0.88 versus 0.1 mmol/100 g). Herbal and traditional plant medicines (14.2), spices and herbs (11.3), berries and berry products (3.34), and vitamin and dietary supplements (3.27), were major sources of APHs (mmol/100 g), but beverages were perhaps the most important contributors to the daily intake of APH, particularly from coffee and its byproducts. It is widely recognized that coffee contains both negative and positive bioactive compounds, but recent evidence indicates a negative dose-response relationship with breast, colorectal, endometrial, and prostate cancer risk as well as other NCCDs (Grosso et al., 2017). Plant foods can be grouped according to the level of APH enrichment. According to Table 11.1, citrus fruits are rich in ascorbic acid, tubers and vegetables in carotenoids, dry oleaginous fruits and seeds in tocols (tocopherols +tocotrienols), and small fruits in monomeric PCs. Tocols are present in several plant foods, including edible oils, nuts, and oleaginous seeds, but their molar distribution is quite unique. For example, good sources of α-tocopherol are green leafy vegetables while soybeans, raspberries, and sunflower seeds are the rich sources of δ-tocopherol (Saini and Keum, 2016). Seeds have 10–20 times more tocols (mainly γ-tocopherol) than leafy vegetables while palm and bran oil, celery, coriander, dill, annatto seeds, and parsley are excellent sources of tocotrienols (Stevens-Barro´n et al., 2017; Shahidi and de Camargo, 2016). As for carotenoids, their natural occurrence and richness are linked to the color of the edible plant foods: β-carotene is abundant in the foods acerola, mango, pumpkin flesh, carrots, and nuts; lycopene in tomato and algae tissues; and lutein and zeaxanthin are present in green and dark green leafy vegetables (Mezzomo and Ferreira, 2016). However, this “APH-rich” generalization does not apply to certain F&V whose APH profile favors several antioxidant groups. For instance, citric fruits are rich sources of both ascorbate and PCs, although not as much as small fruits (berries), where strawberry is also particularly rich in ascorbate (Table 11.1). Initially, the more the APH content, the higher the antioxidant power of plant foods. For example, Olivas-Aguirre et al. (2017) demonstrated that the antiproliferative capacity of mango more than papaya and pineapple against human cervix epithelioid carcinoma

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Table 11.1

Antioxidant composition of common fruits and vegetables.a

Sample

AA

CAT

T

PC

Orange Grapefruit Lemon Tangerine Lime Bitter orange Pineapple Guava Mango Papaya Carrot Pink sweet potato Cantaloupe Squash Pecan White pine nut Pistachio Almond Sunflower seed Strawberry Blueberry Blackberry Raspberry Table grapes Red pomegranate

427.4 380.0 503.3 279.3 326.1 401.5 132.4 1189.1 220.6 510.1 50.4 10.6 372.6 154.5 30.1 0.8 5.8 0.0 1.5 649.7 61.4 177.2 183.9 16.4 46.2

333.3 60.0 13.0 468.5 326.1 618.9 242.9 1.9 3933.3 2311.6 100529 37515.4 20670.1 37233.3 30.1 17.4 259.1 1.0 31.5 77.3 202.7 1080.2 196.5 205.5 0.0

0.3 2.2 2.0 1.2 2.4 1.4 0.0 3.8 5.5 3.5 5.7 1.2 1.6 10.6 27.7 21.0 26.7 28.6 38.6 4.3 6.1 29.1 23.8 1.3 2.7

2381.2 1627.0 777.6 1729.7 2717.4 2060.4 1159.2 658.3 877.4 482.4 494.2 251.1 812.2 251.6 1710.2 388.9 1352.9 301.8 1320.5 3195.6 2583.9 4805.3 1038.7 1783.1 1463.5

AA, ascorbic acid (mg); CAT, carotenoids (μg); T, tocopherols (mg); PC, phenolic compounds (mg of gallic acid equivalents). a Content per 100 g of dry matter. Data source: USDA Nutrient Database (https://ndb.nal.usda.gov/ndb/search/list) and Phenol explorer 3.6 (http://phenol-explorer.eu/).

(HeLa) and murine macrophages transformed by the virus Abelson leukemia (RAW 264.7) was related to the antioxidant activity [α,α-diphenyl-β-picrylhydrazyl (DPPH) radical: EC50 ¼ 4.7, 14.3, 28.0 mg mL1] and their content (per 100 g) in total phenols (9.9, 3.0, 2.7 mg GAE) and ascorbic acid (959, 614, 18 mg), respectively. The same trend was reported by Wang et al. (2011) for vegetables, leguminous seeds, and fruits, observing a different pattern of RSC with DPPH radical, oxygen radical absorbance capacity (ORAC), and ferric reducing antioxidant power (FRAP) methods. It is noteworthy that vitamins A, C, and E are -Bosch, by far more effective antioxidants that other vitamins (Asensi-Fabado and Munne 2010) while PCs have a different antioxidant capacity depending on the spatial distribution and number of aromatic and hydroxyl groups (Palafox-Carlos et al., 2012). The antioxidant capacity of plant foods also depends on the molecular interactions between all APH species present in the same and different (combination) plant foods. It is generally assumed that the overall antioxidant capacity of foodstuffs results from

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the additive effects of all its APHs; however, this is not always true. Palafox-Carlos et al. (2012) evaluated the individual and binary antioxidant capacities of four major PCs present in the Ataulfo mango. They found with the DPPH radical mostly synergistic effects among them, although the gallic acid + vanillic acid combination was antagonistic. According to Wang et al. (2011), the combination of different plant foods more likely results in synergistic effects than the combination of foods from the same food group; when combining foods within the same category (vegetables, leguminous seeds, or fruits) 68%, 21%, and 13% of all binary combinations showed additive, antagonistic, and synergistic interactions, respectively. A fruit combined with either a legume or a vegetable was the most effective synergistic combination. Guimara˜es et al. (2011), also reported that 96 binary combinations of infusions and decoctions prepared with lemon-verbena, fennel, and spearmint herbs and stored 0, 30, 60, and 120 days resulted in 60%, 3%, and 26% synergistic, additive, and antagonistic combinations, respectively. Lastly, the RSC of any APH is related to its physicochemical characteristics (Table 11.2).

Table 11.2

Physicochemical features of common antioxidant phytochemicals.

Compound Vitamin A and Carotenoids Retinol β carotene Lycopene Vitamin C Ascorbic acid Dehydroxyascorbic acid Vitamin E α-Tocopherol β, γ-Tocopherol δ-Tocotrienol α-Tocotrienol β, γ-Tocotrienol δ-Tocotrienol Phenolic compounds Gallic acid Quercetin Epigallocatechin gallate Cyanidin Delphinidin Malvidin Cyanidin-3-O-glucoside Pentagalloyl glucose Punicalagin

MW (g/mol)

TPSA A^2

HBDC (#)

HBAC (#)

XLogP3/miLogPa

286.5 536.9 536.9

20.2 0 0

1 0 0

1 0 0

5.7 13.5 15.6

176.1 174.1

107 101

4 2

6 6

1.6 1.0

430.7 416.7 402.7 424.7 410.6 396.6

29.5 29.5 29.5 29.5 29.5 29.5

1 1 1 1 1 1

2 2 2 2 2 2

10.7 10.3 10.0 9.3 8.9 8.6

170.12 302.2 458.4 287.2 287.2 331.3 484.8 940.7 1084.7

98 127 197 102 102 100 181 444 511

4 5 8 5 5 4 8 15 17

5 7 11 5 5 6 11 26 30

0.7 1.5 1.2 0.75a 0.75a 0.42a 2.79a 3.6 1.7

MW, molecular weight; TPSA, topological polar surface area; HBDC, hydrogen bond donor counts; HBAC, hydrogen bond acceptor counts; LogP, octanol-water partition coefficient; XLogP3, applet on-line predictor; miLogPa, moliinspiration LogP. Data source: Pubchem (https://pubchem.ncbi.nlm.nih.gov/).

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Topological polar surface area (TPSA) and XLogP3 octanol-water partition coefficient (XLogP3) are important indicators of the hydrophilic/hydrophobic nature or a molecule, which in turn influences their absorption behaviors across the intestinal barrier. For the compounds included in Table 11.2, XLogP3 (degree of hydrophobicity) is inversely related to TPSA (ρ ¼0.92) and the number of hydrogen bond donor (HBDC; ρ¼0.84) and acceptor (HBAC; ρ¼0.91) counts and TPSA, HBDC, and HBAC are in turn associated with the antioxidant capacity (Bendary et al., 2013). Hydrophobic APHs (high XLogP3) such as carotenoids and tocols are weaker RSC when compared to hydrophilic APHs such as ascorbate-DHA and PCs. Kim et al. (2002), by using the ABTS radical, demonstrated that the relative antioxidant capacity of gallic acid and quercetin was higher than that of vitamin C, rutin, and chlorogenic acid while Palafox-Carlos et al. (2012) showed the following trend for four phenolic acids using the DPPH radical: gallic > protocatechuic > chlorogenic > vanillic acids. Lastly, the antioxidant contribution of PCs and ascorbate is commonly higher than that coming from tocols and carotenoids, when all of them are present in sufficient amounts as in the case of fruit juices (Yuan and Baduge, 2018).

APH in cancer prevention Several health agencies worldwide recommend an intake of 400 g F&V per day to prevent certain types of cancer and neoplasms (Miller and Snyder, 2012). In 1997, the World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR, 2007) considered as "convincing" the level of scientific evidence that associates a low consumption of F&V with a high risk of suffering from several types of cancer, recommending the daily intake of at least five servings of nonstarchy F&V as a preventive measure (Norat et al., 2014). By 2007, this generalization became probable-convincing for cancers of the upper GI tract and of limited but possible evidence for ovarian, endometrial, lung, liver, pancreas, and colon-rectum cancers. Several observational studies such as the European Prospective Investigation on Cancer and Nutrition (EPIC) confirm the benefits of fruits but not vegetables for cancers of the GI tract and lung, although both (F&V) seem to be ineffective for renal, gastric, pancreatic and biliary tree, and genitourinary cancers (Bradbury et al., 2014). The EPIC study and WCRF/AICR recommend the intake of specific F&V for specific types of cancer such as citrus for stomach (cardia), tubers and garlic for intestinal, and cruciferous for breast cancers (Miller and Snyder, 2012; WCRF/AICR, 2007; Song and Bae, 2013). Also, pure APHs are € ber et al., increasingly used as supplements in preventing and treating several cancers (Gro 2016; Davis et al., 2012). Chemoprevention is the use of drugs, food, or food supplements to prevent disease and its goal in cancer is to reverse or block the carcinogenesis process (Bunaciu and Yen). The individual and complementary actions of specific APHs in cancer prevention have also been documented from cross-sectional and prospective epidemiological studies. Folic acid for pancreatic cancer; carotenoids for oral, pharynx, larynx, and lung cancer; lycopene and PCs for prostate cancer; and vitamin C, pyridoxine, and selenium for esophageal and breast cancer are just some examples (Kotecha et al., 2016; Norat et al., 2014; Bradbury et al., 2014; Song and Bae, 2013).

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However, the evidence derived from controlled clinical studies has not been entirely convincing. For example, in the SU.VI.MAX (Supplementation en Vitamins et Meraux Antioxidants) trial, a multivitamin [vitamins C (120 mg) and E (30 mg), β-carotene (6 mg), selenium (100 μg), and Zinc (20 mg)] showed no effect on all-cause mortality or 7.5 year cancer incidence (Hercberg et al., 2004). Nevertheless, the mechanisms by which these APHs exert their antiproliferative and antitumor effects continue to be elucidated (Kotecha et al., 2016). In the following paragraphs, evidence on the chemopreventive role of APHs against certain cancer cell lines is described, including the metabolomic mechanisms involved. Vitamin A and carotenoids. Carotenoids are hydrophobic (Table 11.2) isoprenoid polyenes categorized as precursors (e.g., α, β-carotene, and β-cryptoxanthin) and nonprecursors (e.g., lycopene) of vitamin A (retinol and retinyl esters). Their color ranges from yellow to red and can be obtained from animals (e.g., retinol), plants and other photosynthetic organisms (carotenoids, apo-carotenoids, and xanthophylls), and bacteria (C30-carotenoids) (Desmarchelier and Borel, 2017; Bunaciu and Yen, 2015; Tanaka et al., 2012). Nearly 40 carotenoids are present in the human diet and their bioaccessibility, although structure-specific, is very efficient (Kopec and Failla, 2018). Vitamin A and carotenoids exert several bioactivities in vision, photo-protection, immunomodulation, antiinflammatory, neuroprotection, and antioxidant and anticancer activities upon cellular deliver-Bosch, 2010). Conversely, vitamin A deficiency causes ing (Asensi-Fabado and Munne several eye illnesses as well as growth retardation, gynecological disorders, and immunodeficiency (Doldo et al., 2015). From a metabolic standpoint, the anticancer activity of carotenoids is as complex as their chemical diversity. Safe pharmacological doses of retinoids reduce the incidence and severity of chemically induced tumors in experimental animals while All-Trans-retinoic acid (ATRA), a retinol metabolite, exerts cytotoxicity and inhibits the proliferation of cervical, stomach, and colon carcinomas (Chinapayan and Prabhakaran, 2019; Doldo et al., 2015; Niles, 2004). ATRA and other retinoids (9- and 13-cis-RA, bexarotene, retinyl palmitate) are effective agents in the prevention and treatment of breast cancer by modulating several growth factor pathways such as EGF/TGF/insulin growth factor (IGF), wingless/integrated-growth-factors (WNT)/NOTCH, PI3K/AKT, and MAPKs signaling pathways (Garattini et al., 2014). Retinoids also prevent many vascular proliferative disorders such as those involved in cancer angiogenesis (Doldo et al., 2015). ATRA and other non-A provitamers (e.g., lycopene) have nuclear (transcriptional, epigenetic) and extranuclear (plasma membrane and cytosolic signaling) actions in cancer cells (Bunaciu and Yen, 2015). ATRA can eliminate cancer stem cells by inducing blast differentiation and cell cycle modulation (Werner et al., 2014) while lycopene modulates gene functions, carcinogen-metabolizing enzymes, apoptosis, and immune function (van Breemen and Pajkovic, 2008). In fact, tomato sauce (high in lycopene) reduces the risk for ERG (+/) prostate cancer (Graff et al., 2016). Also, the antioxidant capacity of α- and β-carotene, β-cryptoxanthin, lutein, and zeaxanthin counteracts the redox stress in other cancer cell lines (Tanaka et al., 2012). Lastly, as in the case of other APHs, the antioxidant and anticancer capacity of carotenoids is structure-specific. Lycopene and lutein possess a much higher activity than

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β-carotene in suppressing colonic tumorigenesis (Narisawa et al., 1996). The risk for breast cancer is reduced in a concentration-dependent manner with the plasma increase of lycopene (0.78) > total carotenoids (0.81) > β-carotene (0.83) > α-carotene (0.87) > β-cryptoxanthin (0.98) in the pooled analysis of the eight prospective studies performed by Eliassen et al. (2012). Vitamin C. From the initial work done by Cameron and Pauling (1976) with massive parenteral infusions of ascorbate (10 g/day) to treat patients with advanced cancer, much information has been published on the anticancer action of this antiscorbutic vitamin and some mechanisms have also been elucidated. From a physiological perspective, ascorbic acid and DHA are actively imported into the endoplasmic reticulum of cells via glucose transporters. In equilibrium, ascorbic acid and DHA play important body functions, including the production of important biomolecules such as collagen and L-carnitine, and their antioxidant activity in protecting cancer cells has been widely documented (Traber and Stevens, 2011). As an APH, ascorbate cross-talk with intracellular levels of H2O2 which is produced in substantial amounts in cancer cells as compared to normal cells (Proprac et al., 2017; Marengo et al., 2016; Phaniendra et al., 2015). Ascorbate exerts epigenetic [e.g., by modulating ten-eleven translocation (TET) enzymes and Jumonji C (JmjC) domain-containing histone demethylases] and cytotoxic effects when used in supraphysiological doses (1 mM). In such a case, a higher than normal level of H2O2 leads to cell cycle arrest, decreased mitochondrial function and energy production, and NrF-2 gene expression and activity (Mastrangelo et al., 2018; Vissers and Das, 2018). Ascorbate also regulates hypoxic response via the α-cetoglutarate-dependent dioxygenase family of enzymes affecting tumor survival, angiogenesis, stem cell phenotyping, and metastasis (Vissers and Das, 2018). Immune cells accumulate high amounts (1.5–3.5 mM) of ascorbate, protecting them from irreversible hypoxic response (via hypoxia-inducible factors) that not only affects their immune function but also their competence against tumor tissues at their inflammatory sites (Ang et al., 2018). Ascorbate also affects the metabolome of different cancer cells by affecting specific metabolic proteins with presumable oncoprotein function such as pyruvate kinase type M2 (PKM2, squamous cell carcinoma), Myc (lymphoma cell lines), Akt, bcl-2 (human lymphoma), Ha-Ras and β-catenin (mutated Ha-Ras mouse), and hepatitis BX-interacting protein (breast cancer MCF7 cells), most of them interfering with glycolysis and glutathione (Park et al., 2018). Ascorbate exhibits cytotoxicity (EC50, μM) against lung (A549) and breast (MCF-7, MDA-MB-468, MDA-MB-231) cancer cells in the range of 272–480 μM but quercetin (a PC) was more effective (155–231 μM). When combined, both APHs reduced the mRNA and protein levels of Nrf2, regardless of the aggressive phenotype of the breast cancer cells (Mostafavi-Pour et al., 2017) Vitamin E. The antioxidant properties of this fat-soluble vitamin were first related to the control of reproductive functions (Marelli et al., 2019). Vitamin E is a consortium of four tocopherols (T, α-, β-, γ-, and δ-tocopherol) and four tocotrienols (T3, α-, β-, γ-, and δ-tocotrienols), collectively known as tocochromanols or tocols; T and T3 differ in

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the number and stereochemistry of methyl groups on the chromanol ring (Saini and Keum, 2016) and saturated (tocopherols) or isoprenoid (tocotrienol) side chains (Shahidi and de Camargo, 2016; Ahsan et al., 2015). The relative antioxidant activity of tocopherols and tocotrienols generally depends on the food system, with α-tocopherol a better APH than γ-tocopherols in oils and fats (Seppanen et al., 2010). Also, the isoprenoid chain confers to T3 a higher capability to penetrate cell membranes with saturated fatty layers (Marelli et al., 2019) such as those found in gynecological tissues. Tocols help to protect the integrity of cell membranes, particularly by reducing the odds of lipid peroxidation (long-chain fatty acids) and cross-talk with ascorbic acid to sustain an effective bi-modal redox system (Stevens et al., 2018; Traber and Stevens, 2011). Vitamin E neutralizes lipophilic (hydroperoxyl) radicals and protects proteins from alkylation, two events of relevance in inflammatory processes. These and other mechanisms are related to the fact that vitamin E deficiency leads to several neuropathic and blood cell disturbances. Other health benefits in NCCDs include neuroprotective, cholesterollowering, and antiinflammatory activities (Marelli et al., 2019). The anticancer effects of tocols have been tested in several tumor cell lines, with γT3 and δT3 the most effective (Constantinou et al., 2019; Marelli et al., 2019). According to Stevens-Barro´n et al. (2017), γT3 > δT3 exhibits antiproliferative, cytotoxic, proapoptotic, and/or cell cycle arrest in pancreas (PANC-1,28, MIA-PACA-2, AsPC-1, BxPC3), colonrectum (HCT-116, DLD-1, SW620, CMT-93, HT-29), breast (MDA-MB-231, MCF7, +SA), lung (A549, H1650), prostate (PC3, LNCap), stomach (SNU-5/16, MKN45), bladder (5637, T24), liver (HepG2), melanoma (B16), and glioblastoma (U87MG) cancer cell lines. In pancreatic cancer cells, δT3 and γT3 upregulate caspases 6, 8, and 9 and inhibit Akt, ERK, and EGF-2 activation, suppressing cell proliferation (Shin-Kang et al., 2011); other molecular targets include NF-κB, P13K/Akt signaling, TGF-β, several cyclins, and P27/ P21 (Marelli et al., 2019). In breast cancer cells, the EC50 of γT3 ranges from 3.0 μM (+SA) to 50 μM (MCF-7) and upregulates P27 and cyclin-dependent quinases (CDK) 2, 4, and 6 while downregulating c-myc, MEK/ERK, Cdc42, cyclin D1, p-glycoprotein (p-gp), actin-related protein (Arp) 2 and 3, and Wiskott-Aldrich Syndrome protein-family verprolin-homologous protein 2 (WAVE2)/Ras-related C3 botulinum toxin substrate 1 (Rac-1) signaling, reducing cancer cell migration and invasiveness (Stevens-Barro´n et al., 2017; Algayadh et al., 2016). Other signaling pathways involved in tocol antiproliferative activity include the inhibition or activation of growth factors (e.g., EGF) and oncogene (e.g., p21, c-myc) mediated pathways, depending on the extent and type of the stimulations (Seppanen et al., 2010). Neovascularization from preexisting capillary vessels (angiogenesis) is a prerequisite for tumor invasion and metastasis (Hanahan and Weinberg, 2011). This process is needed for the proper oxygenation and nutrient supply of neoplastic tissues and the VEGF/VEGFR axis is a major process for angiogenesis. T3 interferes with in situ angiogenic and inflammatory activity by reducing VEGF, IL-6, IL-8, and HIF-1α activity (Marelli et al., 2019); Wells et al. (2010) demonstrated that α- and γ- but mostly δ-tocopherols reduce the odds for angiogenesis and lymphangiogenesis by exerting

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cytotoxic effects (>50 μM), by modifying capillary tube formation, and by reducing endothelial barrier function in immortalized human dermal capillary (HMEC-1) and lymphatic endothelial (HMEC-1A) cells. Lastly, tocols also inactivate several metastatic [e.g., increased matrix metallopeptidase 2 and 9 (MMP-2/9), E-cadherin; reduced TIMP metallopeptidase inhibitors 1 and 2 (TIMP-1/2)], antioxidant (e.g., catalase, Nrf2), and pro- (BAX, caspases) and anti- (e.g., BCL-2) apoptotic proteins, in a tissue- and structure-dependent manner (Stevens-Barro´n et al., 2017). It is noteworthy that tocols control the Nrf2/Keap1 system mainly at the transcriptional level in a structure-dependent manner in prostate (Barve et al., 2009) and aggressive breast cancer (Hsieh et al., 2010) cells. Phenolic compounds (PCs). Hyperproliferation is very characteristic of cancer cells (Hanahan and Weinberg, 2011). PCs affect the carcinogenic process by many mechanisms such as the overexpression of prooxidant enzymes and cell cycle proteins and tumor cell death through apoptotic pathways (Alam et al., 2018; Schnekenburger et al., 2014; D’Archivio et al., 2008). However, the antioxidant and epigenetic activity of PCs in cancer cells depends on their chemical properties and EC50, the cell type and its microenvironment (e.g., pH, Aw), and the oxidative stress status (Hanahan and Weinberg, 2011). Raw extracts from edible fruits have provided initial information as to the anticancer action of certain APHs. For example, anthocyanins from small fruits (berries), particularly delphinidin (Fig. 11.1) and its glycosides, induce concentration- and time-dependent apoptosis in B cell chronic lymphocytic leukaemia (B-CLL) through redox-sensitive caspase 3 activation and Bad/Bcl-2 pathway dysregulation (Alhosin et al., 2015). Delphinidin also induces apoptosis and cell cycle arrest in human colon cancer HCT116 cells at G2-to-M by regulating the p53/p21 axis and cyclin B and cdc2 gene expression (Yun et al., 2009). Olivas-Aguirre et al. (2017) demonstrated that mango Ataulfo pulp APH (namely gallic acid, carotenoids, and ascorbate) has a mild antiproliferative capacity (IC50, μg mL1) against RAW 264.7 (100.7) and HeLa (193.1) cells while Velderrain-Rodrı´guez et al. (2018) confirmed that gallic acid (Fig. 11.1) content and its antioxidant mechanism exert antiproliferative effects on human colon adenocarcinoma LS180 cells. This antiproliferative effect is possibly related to the NF-κBp65 signaling pathway and protein acetylation, as demonstrated by Choi et al. (2009) in A549 cells. Arbizu-Berrocal et al. (2019) recently showed that a mango extract (2.5–10 mg GAE/L) rich in gallic acid, hydroxybenzoic acid hexoside, monogalloyl-glucoside, and penta-to-nona gallotannins inhibited proliferation and ROS generation, reduced inflammation, upregulated miR-126, downregulated miR-21, and modulated the P13K/AKT/mTOR pathway and associated miRNAs in MDA-MB231 and MCF-12A breast cancer cells. In addition, several PCs from green tea (epicatechin), soybeans (genistein), grapes (resveratrol), cocoa (catechin), and turmeric (curcumin) are considered chemotherapeutic agents that modulate chromatin remodeling (Berghe, 2012). Phenolic acids such as gallic, ferulic, coumaric, and caffeic acids (Fig. 11.1) prevent the growth and development of colon cancer cells (e.g., Caco-2, HT-29, HCT15/116, SW-480) by reducing their oxidative stress and inflammatory cyclooxygenases (COX-1, COX-2)

O

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Chapter 11 • Antioxidant phytochemicals in cancer prevention and therapy

HO

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FIG. 11.1 Selected phenolic compounds with anticancer activity. Source: The authors; Epigallocatechin gallate (EGCG), penta-galloyl-glucose (PGG).

while regulating the cell cycle stages (improved G0-to-G1, reduced G2-to-M) and apoptosis (improved Bax:Bcl-2 ratio, Caspase 3 and 8), cell instability [reduced matrix metallopeptidase 9 (MMP-9)], tumor initiation (NF-κB and C-myc), and many other mechanisms (Alam et al., 2018; Rosa et al., 2016). It is noteworthy that the anticancer activity of PCs varies from one compound to another due to their differences in reactive functional groups to establish contact with corresponding target molecules. For example, key functional groups are required for the anticancer effects of phenolic acids such as their aromatic ring and number of hydroxyl groups while those with metoxi groups are less reactive (Anantharaju et al., 2016). That is the reason why gallic acid is more (three dOH, no dOCH3) biologically active than protocatechuic (one dOH, two dOCH3) or p-hydroxybenzoic (one dOH) acids (Alam et al., 2018; Rosa et al., 2016). The chemopreventive effects of dietary flavonoids (and their first-pass metabolic products) are related to several inhibitory or stimulatory effects; these include their antioxidant properties and interactions with protein kinase and lipid kinase signaling pathways

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affecting several cellular functions, molecular phosphorylation, and gene expression (Mansuri et al., 2014). Quercetin and epigallocatechin gallate (EGCG; Fig. 11.1) are possibly the most studied flavonoids with EC50 values ranging from 42 to 80 μM against several colon cell lines (HCT116, HT29, SW480, and SW837) by inhibiting the PI3/AKT, NFκβ, and EGFR families and IAP family pathways while increasing p53 (Alam et al., 2018). Also, malvidin (EC50 72 μg/mL) > pelargodin (154 μg/mL) more than other proanthocyanidins (cyanidin, petunidin, delphinidin) have proven to be effective antiproliferative agents against colon HCT-116 cells, possibly by modulating claudins, MMPs, NF-κB activation, and demethylation of tumor suppressor genes (Alam et al., 2018). Details as to the differential impact of flavonoids in redox homeostasis and cell signaling in normal and cancer cells have been recently reviewed by Kerimi and Williamson (2018). From a physiological perspective, lignans, oligomeric proanthocyanidins, gallotannins, and ellagitannins are not efficiently absorbed in the upper GI tract, reaching the large bowel almost intact (Dominguez-Avila et al., 2017; Velderrain-Rodrı´guez et al., 2014). This is why the interest in complex PCs has been focused mainly on their effect on colorectal cancer. Several proanthocyanidins inhibit angiogenesis while inducing apoptosis on colorectal cancer cells, besides their antioxidant activity (Alam et al., 2018). The lignin arctiin > matairesinol or arctigenin (Fig. 11.1) reduces human SW480 colon cancer cell growth via Wnt/β-catenin (Yoo et al., 2010); the hydrolizable tannin punicalagin (present in pomegranate) releases ellagic acid, causing apoptosis of Caco-2 cells (Larrosa et al., 2006); and pyrogallol, a microbial metabolite from mango gallotannin degradation, suppresses breast cancer ductal carcinoma MCF10DCIS.COM cells by reducing IGF-1R, IR, AKT, IRSS, mTOR, P70S6K, and HIF-1α mRNA and/or protein levels and, in some cases, their corresponding phosphorylated protein levels (Nemec et al., 2016).

APH in cancer therapy The concurrent use of APH and conventional cancer therapy has become a controversy between oncologists and ACM practitioners. The use of tocols to ameliorate radiationinduced mucositis and other adverse effects of radiotherapy as well as retinol palmitate for treating radiation-induced proctopathy while several APHs combined with external beam radiation therapy are increasingly being used as definitive treatments for prostate cancer (Moss, 2007). Current data also support the benefit of supplementation of APHs (e.g., resveratrol and selenium) to improve the immunocompromised condition of cancer patients and reduce the odds for tumor immune invasion (Thyagarajan and Sahu, 2018). However, the socialization of information on the effectiveness of APH supplements among patients with cancer, or among relatives who want to prevent it, has given a new push to this market (Grand View Research, 2016), not always with scientific information to support it (Velicer and Ulrich, 2008; John et al., 2016). In this section, the effectiveness of APHs in clinical practice is discussed. Retinoids have been successfully used in acute promyelocytic leukemia treatment (Bunaciu and Yen, 2015) and breast cancer (Garattini et al., 2014). However, preclinical

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studies in patients suffering from glioma and other conditions have withdrawn retinoids as therapeutic aids (Bunaciu and Yen, 2015). This evidence points to the need for more clinical studies in order to document properly the therapeutic and preventive benefits of retinoid supplementation. Conversely, the level of evidence derived from tumorbearing rodents increasingly supports the positive antitumoral effects of administering large doses of ascorbate. Campbell et al. (2015) fed a mice strain that mimics the human ascorbate dependency condition [C57BL/6 Gulo(/) mice] and supplemented with 33, 330, and 3300 mg/L of ascorbate in their drinking water, before and during subcutaneous tumor growth of melanoma (B16-F10) or lung carcinoma (LL/2. The authors found an inverse relationship between ascorbate and hypoxia-inducible factor-1 (HIF-1) and its target proteins in both tumor-bearing groups. Also, certain preclinical studies have unveiled other ascorbate-sensitive tumors in which ascorbate exerts epigenetic modulation and tumor-killing capacity (Mastrangelo et al., 2018). Oncology patients commonly exhibit a higher requirement for ascorbate, indicating a lower body pool, a higher oxidative stress, and/or a poor proinflammatory status than healthy age-matched controls (Carr and Cook, 2018). Moreover, Nilotinib-based chemotherapy reduces even more the ascorbate body pool of patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Oak et al., 2016), a fact that may also be present in the chemotherapy of other types of cancers. Ascorbate administration decreases leucocyte loss, ascites accumulation, hepatotoxicity, and many other clinical features associated with chemotherapeutic agents (Carr and Cook, 2018). Large doses of ascorbate (10 g/day) administered parentally improve the overall survival of cancer patients (Cameron and Pauling, 1976) and chemotherapy effectiveness (Park et al., 2018; Cimmino et al., 2017). However, Jacobs et al. (2015) performed a Cochrane systematic review of studies published between 1946 and 2014, evaluating the antitumor effect and toxicity of ascorbate treatment. This showed no high-quality evidence to support such benefits, suggesting the need for high-quality placebo-controlled trials. Oral versus parenteral administration of ascorbate does not obviously cause higher plasma bioavailability, but ensures the EC50 needed to increases H2O2 as the therapeutic means to increase ascorbate’s antitumor effects (Mastrangelo et al., 2018; Vissers and Das, 2018). It is noteworthy that ascorbate has been increasingly used by cancer patients either as a dietary supplement or in pharmacological doses administered parenterally, suggesting certain benefits but in the absence of rigorous clinical trial data (Vissers and Das, 2018.) As anticancer agents, tocols (particularly T3) differ in their efficacy by cancer cell type, although their molecular targets and bioactivity seem to be the same. Data derived from in vitro and rodent models sustain that T3 > T targets different mitogenic effectors, protein kinases, transcription factors, cell cycles, and apoptotic proteins while also affecting angiogenesis and metastasis (Constantinou et al., 2019; Marelli et al., 2019; Stevens-Barro´n et al., 2017; Algayadh et al., 2016). However, more preclinical studies supporting a significant effect of tocols during conventional cancer therapy are scarce and so we still cannot conclude anything about it.

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Lastly, PCs have also been postulated as convenient coadjutants in cancer radio/chemotherapy. Ahmad et al. (2010) demonstrated that soy isoflavones could be used to sensitize pancreatic cancer cells to radiotherapy while reducing radiation citoxicity in normal neighboring tissues. Also, the ability to dissipate the mitochondrial membrane potential (Δψm) by protonophore and antioxidant mechanisms has been recently recognized as a dual mechanism by which PCs sensitize tumor cells to apoptosis (Stevens et al., 2018). Such a mechanism is PC-specific, with apigenin, catechin, 2,4-dinitrophenol, EGCG, kaempferol, myricetin, quercetin, and resveratrol just a few of them. However, to date there is no convincing clinical evidence of the role of PCs for inhibiting tumor growth in humans, and results from rodent models cannot be extrapolated. This raises concerns as to whether PCs could be used as coadjutants during cancer therapy.

Metabolic fate of APH Dietary APHs need to overcome many physiological barriers before exerting their anticancer action. Although the lack of effectiveness of APH may be due to many other factors such as the contribution of environmental and food risk factors, the specific cancer metabolome, the Wardburg effect (shifting of the glucose metabolism to anaerobic pathways, even with sufficient oxygen supply) (Tong et al., 2015; Liberti and Locasale, 2016), resistance to antineoplasic effectors, or the subject’s genetic predisposition, the chemical nature of each APH, its bioaccessibility (release ability from food matrices), and first-pass metabolism (quantity and postabsorption modification) are also determinants (Dominguez-Avila et al., 2017). In plant tissues, APHs are compartmentalized in different organelles or complexed with cell wall macromolecules. Consequently, there is a direct relationship between the denaturing degree of plant food matrices by physical (e.g., thermal-ultrasound processing, enzymatic hydrolysis) and GI-simulated methods with the amount of APH released from food matrices (Velderrain-Rodrı´guez et al., 2014; Dominguez-Avila et al., 2017). As an example, a substantial amount of β-carotene is released during hard cooking or kitchen blender homogenization (Lemmens et al., 2010). The same behavior has been observed in hydrophilic compounds such as ascorbic acid and anthocyanins (Leong and Oey, 2012). Also, the intermolecular bond disruption occurs during the gastrointestinal passage, increasing the surface area of the dietary macromolecules [e.g., Mucin (MU), dietary lipids (DL), protein (DP), and fiber (DF)] and enhancing APH accessibility and intestinal permeability in a structure-dependent manner (Pacheco-Ordaz et al., 2018; Guo et al., 2013; Lemmens et al., 2010). Particularly, the bioaccessibility and enteric absorption of carotenoids and xanthophylls is promoted by high methoxy pectins, edible oils, certain PCs, bile salts, and breast milk but inhibited by low methoxy pectin, flavanones, divalent metals, and vitamins D, E, and K (Kopec and Failla, 2018). Bioaccessible APHs within the intestinal lumen are further absorbed or biotransformed. Lipophilic APHs (Vitamins A and E) incorporated into micelles are more likely

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to be absorbed by passive diffusion (Velderrain-Rodrı´guez et al., 2014), but certain carotenoids and tocols are also actively transported via Class B scavenger receptors (SCARB), scavenger receptor B1 (SRB1), cluster of differentiation 36 (CD36), and Niemann-Pick C1-like protein 1 (NPCIL1). Fat-rich foods promote the efficient micellization of carotenoids, tocols, and nonpolar PCs, mainly in their aglycone form (Guo et al., 2013; Dominguez-Avila et al., 2017). The entry and trafficking of carotenoids within enterocyte and internal organ cells are mediated by a well-organized set of proteins, for example, the internalization and trafficking of retinoids and xantophyls in enterocytes by several cellular receptors including scavenger receptors and retinol binding proteins (Doldo et al., 2015). Glycosylated polyphenols (e.g., Cyanidin-3-O-glycoside) seem to be efficiently absorbed by its sugar moiety by many glucose transporters (e.g., GLUTs, SGLTs), depending on the initial dose (Dominguez-Avila et al., 2017; Zou et al., 2014). Ascorbate is absorbed by Na-dependent vitamin C transporters (SVCT1, SVCT2) in a structuredependent manner (Vissers and Das, 2018). As a result of all the aforementioned events, the luminal bioaccessibility of APH will vary greatly and so it’s the amount delivered to the systemic circulation (Manach et al., 2005). Once within small bowel enterocytes, all these APHs are returned back (efflux), biotransformed (e.g., β-carotene to retinal), or repacked for basolateral transport in a structure-dependent manner, upon systemic needs. Lipophilic APHs are more likely to be packed into chylomicrons and transported in the lymph (Desmarchelier and Borel, 2017); meanwhile, hydrophilic APHs are rarely absorbed in their native form because they are transformed by many brush border enzymes. Once within the enterocyte, they are subject to other conjugations by the mitochondrial cytochrome p450 (Velderrain-Rodrı´guez et al., 2014). Many phenolic metabolites will be handled as any other xenobiotic and everted to the apical side by p-glycoproteins or ABC proteins before entering the portal vein (Li and Paxton, 2013). The absorption efficiency of carotenoids in internal organs will be in part determined by the expression of putative membrane transporters such as SR-BI or CRBP (Desmarchelier and Borel, 2017). According to Vissers and Das (2018), there is a very low accumulation of ascorbate within cells when the plasma level is between 50 and 100 μM. Therefore, supraphysiological levels are required to reach enough intracellular levels of ascorbate to perform any anticancer bioactivity. Most tocols are packed into chylomicrons and rapidly distributed in peripheral tissues, but RRR-α-tocopherol has a long plasma half-life (48–60 h) due to an efficient hepatic recirculation via α-Tocopherol transfer protein (α-TTP). Circulant PCs (metabolites and parent compounds) travel in the bloodstream as aglycones until reaching the liver, where they are subject to phase-II transformation (Dominguez-Avila et al., 2017). It is noteworthy that the EC50 and plasmatic half-life (0.8–16.3 h; Dominguez-Avila et al., 2017) of PCs greatly depend on their chemical nature and ability to escape from phase-II biotransformation (Li and Paxton, 2013). According to Manach et al. (2005), the plasma concentration of total metabolites ranges from 0 to 4 μM with an intake of 50 mg aglycone equivalents. Also, the intestinal absorption and urinary

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excretion are structure-dependent (gallic acid and isoflavones > catechins, flavanones and quercetin glycosides > galloylated catechins and anthocyanins). Lastly, EC50 represents the concentration of a chemical compound where 50% of its maximal effect is observed. While the EC50 values of antineoplastic drugs are typically in the nM to mM range, the maximum concentration (Cmax) of purified plant APH is sometimes 10–100 times higher (Dominguez-Avila et al., 2017; Vissers and Das, 2018). Therefore, it would be necessary to use enteral formulations or parenteral administration to make their systemic delivery more efficient, as has been reported for beta-carotene (Gasa-Falcon et al., 2019) and PCs (Velderrain-Rodrı´guez et al., 2019). Such differences are not only due to the aforementioned bioaccessibility/bioavailability factors, but also on the chemical affinity of APH toward target molecules and its individual REDOX behavior. For example, a plasma ascorbate concentration ranging from 40–80 μM acts to enhance plasma antioxidant capacity while at a higher concentration (mM range), it acts as a prooxidant (Park et al., 2018; Vissers and Das, 2018). As for vitamin E, current evidence states that tocotrienols (particularly δ and μ isoforms) are much more effective than tocopherols (Constantinou et al., 2019) but very few natural sources or nutraceuticals are rich in tocotrienols (Stevens-Barron et al., 2017; Kotecha et al., 2016).

APHs as prooxidants Several international organizations recommend consuming plant foods in a certain amount and variety to prevent certain types of cancer (Miller and Snyder, 2012; WCRF/ AICR, 2007; Song and Bae, 2013). The anticancer action of plant foods is in part due to their richness in APH with defined molecular mechanisms. However, while several public campaigns such as "five a day" make efforts to increase the consumption of F&V at the population level, the scientific advance in the identification of APHs with antiproliferative capacity against different cancer cells does not seem to contribute to benefits of plant foods on cancer therapy. Those scientific advances include studies on APH pharmacodynamics and small but substantial evidence derived from prospective cohort studies, randomized clinical trials, and in vitro models, On the contrary, there is emerging evidence that certain APHs may stimulate tumor cells to grow (Tong et al., 2015), and so they are currently in the "eye of the hurricane." In the last five years, a new controversy has emerged over the fact that certain APHs are indeed prooxidants under certain circumstances. This hypothesis is supported by several randomized clinical trials in which APHs are administered parenterally or are enteral protected drugs (Miliukiene_ et al., 2014; Miller and Snyder, 2012; Yang et al., 2012). Apparently, the prooxidant activity of gallic and ascorbic acids occurs at supraphysiological concentrations, mainly due to the strong RSC and weak metal chelating ability (Yen et al., 2002). Carotenoids and their metabolites are also subject to ROS/NOS oxidative reactions, influencing their activity in such a dynamic way that it is very difficult to catch their preference toward one specific mechanism in vivo (Ribeiro et al., 2018). At high concentrations, α-tocopherol is prooxidant in vitro (Fenton reaction) upon the presence of

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transition metals and induces the apoptosis of several cancer cells (Stevens-Barron et al., 2017; Kotecha et al., 2016), but also increases the risk for lung adenocarcinoma and bone rez-Torres et al., 2017). alterations (Pe This evidence supports the initial recommendation made by the World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR, 2007) on avoiding the consumption of pure supplements and favoring the consumption of F&V or other foods that contain them naturally (Table 11.1). Anyhow, there is still a long way to go before firmly establishing the noneffectiveness of APH-based nutraceuticals.

Conclusion Cancer establishment and progression require cancer cells to possess six capabilities, all of them involving changes in their redox state. APH-based therapies should not only be selective in reducing the likelihood of cancer progression, but also not be against the action of conventional therapies (radiotherapy, chemotherapy). Moreover, APH consumption should be perceived as a positive ACM therapy by physicians and patients who use them. From a prospective view, this represents a challenge given that evidence from in vitro, ex vivo, and in vivo (experimental animals) studies offers a promising scenario, but more conclusive preclinical studies are needed in clinical practice.

Acknowledgments The authors are thankful to the National Council of Science and Technology for funding the Project “Antioxidants from fruits and vegetables in cancer: Are their bioaccessibility, bioavailability or structural synergism responsible for their inefficiency?” (CB-2015-1/254063).

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Further reading Michaelis, L., 1939. Free radicals as intermediate steps of oxidation-reduction. Cold Spring Harb. Symp. Quant. Biol. 7, 33–49. Teixeira, F.J., Santos, H.O., Howell, S.L., Pimentel, G.D., 2019. Whey protein in cancer therapy: a narrative review. Pharmacol. Res. 144, 245–256. Yasueda, A., Urushima, H., Ito, T., 2016. Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: a systematic review. Integr. Cancer Ther. 15 (1), 17–39.

12

Prooxidant anticancer activity of plant-derived polyphenolic compounds: An underappreciated phenomenon Husain Y. Khana, Sheikh Mumtaz Hadib, Ramzi M. Mohammada, Asfar S. Azmia a

DEPARTMENT OF ONCOLOGY, WAYNE STAT E UNI VER S IT Y S CHOO L O F MEDI CINE , D ET RO IT , MI , UNI TE D STATE S b DEPARTMENT OF BIOCHEMI STRY, ALIGARH MUSLI M UNI VERSI TY, ALIGARH, INDIA

Introduction Cancer is one of the most lethal diseases, accounting for almost 16% of all mortalities worldwide (https://www.who.int/features/factfiles/cancer/en/). According to the World Health Organization (WHO), around 9.6 million people were estimated to have died of cancer worldwide in 2018 (https://www.who.int/cancer/en/). There are several probable causes of cancer. The major environmental causes of cancer include exposure to certain cancer-causing chemicals, radiation, and viruses. Also, some individuals inherit certain mutated genes that make them predisposed to develop particular cancers at some point in their lives. Besides the environmental and genetic causes, there are many risk factors associated with lifestyle such as smoking, tobacco chewing, excessive alcohol consumption, dietary habits, and physical inactivity that contribute to cancer development (https://www.cancer.org/cancer/cancer-causes.html). In spite of being one of the common causes of mortality across the globe, cancer is believed to be a partly preventable disease that is susceptible to modulation by dietary factors. Foods, dietary patterns, nutrients, and other dietary constituents are associated with the risk for several types of cancer. In fact, it has been estimated that through appropriate lifestyle changes including dietary modifications, almost one-third of all cancers can be prevented (Doll and Peto, 1981; Manson, 2003). Interestingly, cancer-protective effects have been reported for people eating fruits and vegetables in high quantities in comparison to those who consume fewer plant-based products in their diets (Pavia et al., 2006). Several epidemiological and animal studies have reported that consumption of foods rich in vegetables and fruits reduced the incidence of some cancers, suggesting Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00012-0 © 2020 Elsevier Inc. All rights reserved.

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that certain dietary factors may contribute to cancer-preventive effects (Reddy et al., 2003; Benetou et al., 2008; Freedman et al., 2008). It is also well known that a Mediterranean dietary pattern, which is marked by a high content of phenolic antioxidants, has beneficial effects on health, particularly in cancer prevention (Russo et al., 2014). Plant polyphenols constitute a prominent class of phytochemicals of which plantderived foods and beverages are rich. A wide variety of polyphenols are present in vegetables, fruits, grains, and beverages such as green tea and red wine. They have garnered a lot of interest in the scientific community and have received much attention over the last three decades, owing to their reported health benefits, particularly anticancer effects. In addition to their cancer chemopreventive properties, a wide range of other pharmacological properties such as cardioprotective, neuroprotective, and antiinflammatory effects have also been attributed to polyphenols (Thomasset et al., 2007; Ullah and Khan, 2008). It is also noteworthy that many polyphenolic compounds have been implicated as active constituents in various herbal and traditional medicines. Plant polyphenols are structurally diverse and more than 8,000 different polyphenols have been identified so far (Del Rio et al., 2013). They have at least one aromatic ring in their structure with one or more hydroxyl groups attached to it. Fig. 12.1 illustrates the structures of some of the representative polyphenolic compounds. Polyphenolic compounds are secondary metabolites that function as components of a plant’s defense against predation by herbivores, insects, and microorganisms. They also help protect plants from UV radiation while attracting pollinators and acting as allelopathic agents and signal molecules in nitrogen-fixing root nodule formation (Del Rio et al., 2013). For humans, plant polyphenols hold significance as nonnutritive constituents of their diet. Although they are not essential for our health in the short term, there is evidence to suggest that long-term modest consumption can reduce the incidence of

FIG. 12.1 Some common dietary polyphenolic compounds and their structures.

Chapter 12 • Prooxidant anticancer activity of plant-derived polyphenolic

certain cancers and other chronic diseases. Some of the most broadly studied dietary polyphenolic compounds with known cancer chemopreventive properties are resveratrol (present in red grapes and red wine), curcumin (found in turmeric), quercetin (present in onions), epigallocatechin gallate (present in green tea), and genistein (found in soybeans). Several epidemiological and clinical studies have found a correlation of polyphenol consumption with a reduced risk of different cancers in healthy individuals or a decline in cancer recurrence in patients (Key et al., 1999; Arts et al., 2002; Su and Arab, 2002; Le Marchand et al., 2000). Moreover, many polyphenols have been shown to induce apoptosis and cell cycle arrest in various types of cancer cells (Chen et al., 2017; Gao et al., 2018; Zhang et al., 2013). Therefore, numerous polyphenolic compounds belonging to various subclasses such as stilbenes, isoflavones, gallocatechins, curcuminoids, and tannins have been identified as possessing cancer chemopreventive properties (Ramos, 2007; Shimizu et al., 2015; Surh, 2003). Although the mechanisms through which different polyphenols induce anticancer effects have been studied with considerable interest, a clear understanding on the subject is still lacking. Numerous mechanisms of action have been suggested through which different polyphenolic compounds may exert their anticancer effects. Specifically, some of the widely reported anticancer mechanisms of polyphenols include antioxidant action (Kang et al., 2019; Das and Vinayak, 2015), modulation of enzymes associated with carcinogen activation and detoxification (Das and Vinayak, 2015; Schwarz and Roots, 2003), cell cycle arrest (Gao et al., 2018; Zhu and Bu, 2017), induction of apoptosis (Teekaraman et al., 2019; Zhou et al., 2017; Zhu and Bu, 2017), modulation of gene expression (Couture et al., 2019), modulation of cellular signaling pathways (Kowshik et al., 2014; Srivastava and Srivastava, 2019; Zhou et al., 2017), antiinflammatory action (Das and Vinayak, 2015), antiangiogenic action (Liu et al., 2017; Zhao and Hu, 2013) and antimetastatic action (Ho et al., 2019; Kimura and Sumiyoshi, 2016; Sun et al., 2019). It may be noted that most of the mechanisms suggested to be responsible for polyphenol-mediated cancer cell death implicate the modulation of gene expression and cellular signaling by polyphenols that leads to growth inhibition, apoptosis, or cell cycle arrest in cancer cells. However, a single mechanism that can account for the observed similar anticancer effects of different polyphenolic compounds with diverse chemical structures needs to be explored. In this regard, we have proposed a prooxidant action of polyphenols that involves the mobilization of intracellular copper to be a common mechanism that may possibly explain the anticancer properties of various polyphenols (Hadi et al., 2000, 2007). Since the time this mechanism was put forth almost two decades ago by Hadi et al. (2000), it has been looked at with skepticism while remaining largely underappreciated. But, as we proceeded to successfully validate this hypothesis over the years and with the emergence of more evidence for a prooxidant behavior of polyphenols, the concept has steadily gained momentum and an ever-increasing realization of the prooxidant activity of polyphenols has been seen of late. Here, we will discuss this prooxidant anticancer

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action of polyphenols and enumerate the experimental proofs obtained by our group over the past several years that have helped to establish and strengthen our idea.

Cancer chemoprevention and polyphenols Cancer chemoprevention is described as the pharmacological use of naturally obtained or synthetic nontoxic compounds to prevent, inhibit, or reverse the process of cancer development (Boone et al., 1997). It is believed that an ideal chemopreventive compound should be selective for cancer cells and evince a significant bioavailability. Such a molecule should also be easy to administer and inexpensive, yet highly effective. Plant polyphenols appear quite attractive in this context due to their relative lack of toxicity and easy availability. In addition, several polyphenolic compounds have been found to show preferential cytotoxicity toward neoplastic cells rather than against normal cells. For example, epigallocatechin gallate (EGCG), which is the most common green tea polyphenol, was able to induce internucleosomal DNA fragmentation in various types of cancer cell lines representing mouse lymphoma, human prostate carcinoma, human epidermoid carcinoma, and human keratinocyte carcinoma (Ahmad et al., 1997). Such DNA fragmentation was, however, not seen in normal human epidermal keratinocytes (Ahmad et al., 1997). Similarly, some studies have demonstrated that red wine polyphenol resveratrol and soy isoflavone genistein could induce apoptosis in different cancer cell lines but not in normal cells (Clement et al., 1998; Chang et al., 2008). Physiological concentrations of genistein have been reported to cause reduced growth and induction of apoptosis in cancer cells (Moiseeva et al., 2007). Furthermore, polyphenolic compounds have been found to sensitize cancer cells to chemotherapeutic drugs (Fulda and Debatin, 2004; Santandreu et al., 2011) and radiotherapy (Hillman and Singh-Gupta, 2011). Polyphenols are capable of scavenging free radicals formed by xenobiotics and radiation as well as those oxygen radicals that are generated endogenously. This ability is considered to be the basis of most of the pharmacological properties of polyphenols. However, some evidence from the literature indicates that the anticancer effects of polyphenols may not be completely explained by their antioxidant properties (Hadi et al., 2000; Elbling et al., 2005). Ellagic acid, despite being 10 times more potent an antioxidant than tannic acid, was found to be less effective than tannic acid in inhibiting the promotion of skin tumors by 12-O-tetradecanoyl phorbol-13-acetate. So, it was concluded that the antioxidant effects of these polyphenolic compounds might be essential but not sufficient for their antitumor promotion properties (Gali et al., 1992). According to conventional wisdom, polyphenols are thought to act as antioxidants and this activity is considered to be primarily behind their cancer-preventive effects. However, cancer regression has also been shown to be induced by polyphenols (Carbo et al., 1999; Aziz et al., 2003) and such a therapeutic action cannot be explained by an antioxidant mechanism. Therefore, it is envisaged that antioxidant properties of polyphenols may account for their chemopreventive action but not for any therapeutic effects against cancer (Radin, 2003).

Chapter 12 • Prooxidant anticancer activity of plant-derived polyphenolic

A copper-mediated prooxidant anticancer mechanism of polyphenols Most antioxidants of plant origin are redox (reduction-oxidation) active in nature, rendering protection against free radicals under some circumstances while promoting their generation under others (Herbert, 1996). In other words, they possess both antioxidant and prooxidant properties. Several studies from our laboratory have previously demonstrated that polyphenolic compounds in the presence of copper ions can act as prooxidants, causing breakage of DNA via ROS generation (Ahmad et al., 1992, 2000, 2005; Khan and Hadi, 1998; Ahsan and Hadi, 1998; Azam et al., 2004). Zheng et al. (2006) also demonstrated that resveratrol and its certain synthetic analogues, which behave as effective antioxidants otherwise, can switch to become prooxidants in the presence of Cu(II) ions and cause DNA damage. This type of oxidative DNA breakage induced by polyphenols correlates with their ability to induce apoptosis. It should also be noted that the apoptosis triggered by polyphenols has been reported to be accompanied by an increment in intracellular levels of ROS, formed possibly as a result of the reduction of transition metal ions in cells (Yoshino et al., 2004; Eghbaliferiz and Iranshahi, 2016). Further, it is also known quite well that the apoptotic DNA fragmentation induced by many clinical anticancer drugs (Kaufmann, 1989; Tsang et al., 2003; Kim et al., 2006) and γ-radiation (Sellins and Cohen, 1987) is mediated by ROS. In this regard, it is important to mention that certain properties of polyphenols, such as DNA binding and its breakage and ROS formation in the presence of transition metal ions (Rahman et al., 1990), are apparently quite similar to those of some clinically used anticancer drugs (Ehrenfeld et al., 1987). Therefore, there is substantial evidence in the literature to indicate that the prooxidant activity of polyphenols may possibly be the major mechanism of their anticancer properties. Based on our own observations and considering those of others, we proposed a novel mechanism according to which polyphenolic compounds mobilize intracellular copper ions in cancer cells, leading to oxidative DNA breakage and consequent cell death. It was also proposed that the selective cytotoxicity of polyphenols toward cancer cells may be explained by the elevated copper levels in cancerous tissues and cells (Khan et al., 2012). Copper is one of the most redox active metal ions present in the human body. It is a major metal of the cell nucleus, where it is known to be closely bound to chromatin. Based on reports of altered copper distribution in tumor-bearing mice, rats, and humans (Apelgot et al., 1986; Semczuk and Pomykalski, 1973), the role of copper has been extensively studied in tumor etiology and growth (Brewer, 2005). Interestingly, copper levels in the sera and tumors of cancer patients have been reported to be considerably elevated in comparison to those of healthy individuals (Gupte and Mumper, 2009). A number of studies have also determined the concentrations of iron, copper, zinc, and selenium in cancer patients. The levels of copper were almost always found to be significantly increased (up to 2–3 times) while zinc, iron, and selenium concentrations were substantially lower in cancer patients as compared to age-matched tissue samples from normal individuals

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(Kuo et al., 2002; Zuo et al., 2006). Further, such an increase in copper levels has been shown to have a direct correlation with cancer progression. Copper is believed to aid angiogenesis, which is important for tumor growth and development (Finney et al., 2009). It has been observed that copper depletion leads to a reduced expression of several angiogenic cytokines and growth factors (Finney et al., 2009). In addition, it has been shown in vitro that copper can stimulate the motility of endothelial cells and is also capable of inducing the synthesis of a matrix glycoprotein, fibronectin, that is involved in angiogenesis (Gupte and Mumper, 2009). Moreover, the major copper-binding protein ceruloplasmin, incidentally also elevated in cancer, has been found to be an endogenous stimulator of angiogenesis and helps in tumor neovascularization (Brewer, 2005). This could be a reason for the elevated copper levels seen in tumors. Several other lines of indirect evidence, suggesting strongly that the redox cycling of copper mediates the prooxidant action of polyphenols and may provide an important mechanism for their anticancer effects, have been discussed in detail in a previously published review article (Hadi et al., 2010). The elevated levels of copper in cancer cells have, therefore, been identified as a potential target for the cancer cell-specific anticancer activity of plant polyphenols. In confirmation of our idea that plant polyphenols induce a copper-mediated prooxidant anticancer action, several milestones have been achieved so far. In Table 12.1, we list the key experimental proofs obtained in our lab over the years toward validating our hypothesis. Such findings are discussed in detail in the succeeding sections. Table 12.1 Experimental evidence to support the copper-mediated prooxidant anticancer action of polyphenols. S. No.

Experimental findings

Ref.

1.

A reaction between polyphenols, Cu (II), and DNA leads to DNA cleavage in vitro

2.

Polyphenol-Cu (II) is capable of causing DNA breakage in a cellular system Polyphenols can mobilize endogenous copper ions from cells, leading to oxidative cellular DNA degradation Nuclear copper is mobilized in the polyphenol-induced oxidative cellular DNA degradation Oral administration of copper to rats results in enhanced prooxidant cellular DNA breakage by polyphenols Polyphenols induce growth inhibition and apoptosis in cancer cells through copper redox cycling and ROS generation Supplementation with copper sensitizes normal breast epithelial cells to antiproliferative action of polyphenols Polyphenol-induced prooxidant anticancer activity is enhanced at acidic pH associated with cancer cells

Ahmad et al. (1992), Khan and Hadi (1998), Ahsan and Hadi (1998), Ahmad et al. (2000), Azam et al. (2004) Azmi et al. (2005)

3. 4. 5. 6.

7. 8.

Azmi et al. (2006), Bhat et al. (2007) Shamim et al. (2008), Ullah et al. (2009) Khan et al. (2011) Ullah et al. (2011), Khan et al. (2014), Zubair et al. (2016) Khan et al. (2014), Farhan et al. (2016) Shamim et al. (2012), Ullah et al. (2016)

Chapter 12 • Prooxidant anticancer activity of plant-derived polyphenolic

Oxidative DNA breakage induced by polyphenols in the presence of copper ions in vitro Initial studies from our lab have established that various types of polyphenols, including flavonoids (Ahmad et al., 1992), resveratrol (Ahmad et al., 2000), gallocatechins (Azam et al., 2004), curcumin (Ahsan and Hadi, 1998), and tannic acid and its structural constituent gallic acid (Khan and Hadi, 1998), have the ability inflict oxidative DNA strand breakage, either alone or in the presence of copper. It was also shown earlier that polyphenols can bind to DNA and copper (Ahsan and Hadi, 1998; Rahman et al., 1990), and upon binding to copper ions, polyphenols can catalyze their redox cycling (Hanif et al., 2008). It is believed that a ternary complex is formed when polyphenols bind to DNA and copper ions (chromatin bound). In this ternary complex, as shown in Fig. 12.2, a redox reaction may occur between polyphenol and Cu(II), resulting in the reduction of Cu(II) to Cu(I), whose reoxidation by molecular oxygen leads to ROS generation. These ROS finally act as effectors of DNA breakage, which consequently leads to cell death. Resveratrol has been shown to reduce Cu(II) to Cu(I) and the stoichiometry of Cu(I) formation does not exhibit a clear maximum absorption plateau, which points toward a possible redox cycling of copper ions by the polyphenol (Ahmad et al., 2000). Therefore, it implies that the redox cycling of copper ions is an essential aspect of the copper-mediated oxidative DNA damage induced by polyphenols. The ability of the polyphenol-Cu (II) combination to induce oxidative DNA breakage in a cellular system was confirmed in isolated human peripheral lymphocytes using alkaline single cell gel electrophoresis, also known as the comet assay (Azmi et al., 2005). It was further demonstrated that ROS scavengers and a Cu(I)-specific chelating agent, neocuproine, could inhibit this polyphenol-induced cellular DNA breakage. These findings established that the polyphenol-Cu(II) combination for oxidative DNA breakage is

DNA-Cu(II)-Polyphenol

DNA-Cu(I)-Polyphenol



H2O2

O2– 2H+



O2–

O2



O2– O2 HO• HO–

DNA damage

Cell death

FIG. 12.2 A proposed schematic representation depicting the formation of a ternary complex involving polyphenol, DNA, and copper, whose redox cycling generates various ROS that can cause DNA breakage and consequent cell death.

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physiologically feasible and may hold biological relevance. Later, it was observed that polyphenol alone (without any exogenous copper) at higher concentrations could cause oxidative breakage of cellular DNA and that such DNA breakage was mediated via mobilization of endogenous copper (Azmi et al., 2006; Bhat et al., 2007).

Polyphenols mobilize nuclear copper to mediate prooxidant DNA damage We used intact lymphocytes and isolated lymphocyte nuclei to demonstrate that polyphenolic compounds mobilize chromatin-bound copper, which leads to redox cycling of copper ions and oxidative DNA breakage (Shamim et al., 2008). This observation was reaffirmed by another study in which permeabilized cells were used instead of cell nuclei (Ullah et al., 2009). Permeabilized cells contain only organelles attached with the residual cytoskeleton, and hence, allow a direct interaction of polyphenols with the nuclei. This direct interaction expectedly resulted in significantly higher DNA breakage in permeabilized cells in comparison to intact cells. Mobilization of chromatin-bound copper and its redox cycling leading to ROS generation has been implicated as the molecular basis for such DNA breakage. Polyphenol-induced DNA degradation in the presence of the Cu(I)-specific chelators neocuproine and bathocuproine was examined in intact as well as permeabilized lymphocytes (Ullah et al., 2009). Polyphenol-induced DNA breakage in intact lymphocytes was inhibited upon incubation of lymphocytes with a cell membrane permeable copper sequestering agent, neocuproine. Such inhibition was not caused by the membrane impermeable copper chelator, bathocuproine sulfonate. In permeabilized cells, however, both the copper chelators were able to inhibit DNA degradation in a concentrationdependent manner. This was not unexpected as both the chelators could traverse through the permeabilized cells to permeate the nuclear pore complex and would be able to directly interact with chromatin-bound copper. It was, therefore, concluded that the mobilization of nuclear (chromatin-bound) copper is involved in the polyphenol-induced prooxidant cellular DNA breakage.

Inducing high copper levels in lymphocytes leads to increase in polyphenol-induced DNA breakage As copper levels are known to be significantly elevated in cancer cells, an attempt was made to simulate similarly high copper concentrations in normal lymphocytes by orally administering copper to rats (Khan et al., 2011). It was found that oral administration of copper to rats resulted in increased levels of copper in the serum and lymphocytes. When such lymphocytes with a copper overload were treated with either resveratrol, EGCG, or genistein, an increase in DNA breakage was seen. Also, treating the isolated rat lymphocytes with increasing concentrations of the polyphenolic compounds led to a progressive increment in DNA breakage. However, such enhancement in cellular DNA breakage was more prominent in the lymphocytes of copper-administered rats in comparison to those

Chapter 12 • Prooxidant anticancer activity of plant-derived polyphenolic

from untreated animals. This indicates the involvement of endogenous copper in the polyphenol-induced cellular DNA breakage.

Polyphenol induced cell death in cancer cells occur through mobilization of intracellular copper and generation of ROS As described above, using isolated human peripheral lymphocyte and copper-overloaded rat lymphocyte models, it has been firmly established that polyphenols can induce cellular DNA breakage through the mobilization of nuclear copper ions that leads to ROS generation. Studies from our lab on cancer cell models have demonstrated that a similar prooxidant mechanism of action also plays a pivotal role in the polyphenol-induced apoptosis and growth inhibition in cancer cells (Ullah et al., 2011; Khan et al., 2014; Zubair et al., 2016). Such apoptosis induction and cell growth inhibition by polyphenols in cancer cells has been shown to be considerably abrogated by the copper chelator, whereas iron and zinc chelators turned out to be relatively ineffective. This confirmed the role of intracellular copper ions and ruled out the involvement of other metal ions such as iron or zinc in polyphenol-induced cytotoxicity toward cancer cells. The effect of different ROS scavengers on polyphenol-induced growth inhibition and apoptosis in cancer cells was also studied (Ullah et al., 2011; Khan et al., 2014; Zubair et al., 2016). All the scavengers of ROS were found to be able to cause significant inhibition of polyphenol-induced antiproliferative activity in cancer cells, attesting to the idea that ROS act as effectors of polyphenol-induced apoptosis. Therefore, it was concluded that the anticancer effect of polyphenols involves a prooxidant action that leads to cell death. Some other studies, in which polyphenols such as resveratrol have been shown to exhibit prooxidative action in cancer cells, support our findings (Santandreu et al., 2011). Similar results obtained with various polyphenols tested on different cancer cell lines in our lab strengthen the notion that this copper-dependent prooxidant cytotoxic action against cancer cells is possibly a mechanism common for most, if not all, of the polyphenolic compounds. It has also been observed that while cancer cells, upon treatment with polyphenols, experience growth inhibition, noncancerous epithelial cells remain relatively unaffected. We have found that genistein could induce a time- and dose-dependent inhibition of breast cancer cell proliferation, but not in normal breast epithelial cells (Ullah et al., 2011). Intriguingly, no detectable copper was shown to be found in these normal breast epithelial cells (Daniel et al., 2005). This can account for their aversion to the polyphenol-induced cell growth inhibition. Moreover, this cancer cell selective cytotoxicity of polyphenols may be explained by the fact that copper levels in cancer cells are substantially enhanced. We have also demonstrated that culturing normal breast epithelial cells (MCF10A) in a copper-enriched medium sensitizes such cells to polyphenol-induced growth inhibition and an increased expression of Ctr1 (a membrane-bound copper transporter) (Khan et al., 2014). This observation assumes significance in view of the fact that copper transporters are also overexpressed in cancer cells, which can lead to the uptake and accumulation of

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excess copper in those cells (Brewer, 2005). Therefore, it was concluded that higher Ctr1 expression in copper-enriched MCF10A cells (simulating the copper redox status of cancer cells) aided the accumulation of exogenous copper and resulted in the sensitization of the cells toward enhanced growth inhibition by polyphenols (Khan et al., 2014; Farhan et al., 2016).

Copper-mediated prooxidant anticancer action of polyphenols is augmented at acidic pH microenvironment associated with tumors Epithelial tumors are known to have lower pH compared to normal tissues due to lack of vasculature, hypoxia, and a heightened rate of glycolysis and lactate fermentation (Gerweck and Seetharaman, 1996). Interestingly, resveratrol-induced apoptosis in pancreatic cancer cells and DNA degradation in lymphocytes has been shown to be enhanced at acidic pH (Shamim et al., 2012). This study implied a copper-dependent prooxidant mechanism to be responsible for the DNA-damaging and apoptosis-inducing activities of resveratrol at the acidic pH of cancer cells. Similarly, another study from our group demonstrated that hypoxia-induced intracellular acidification enhances the sensitivity of cancer cells to the cytotoxic effects of daidzein and that such anticancer action involves the mobilization of nuclear copper by daidzein, which results in prooxidant cell death (Ullah et al., 2016). These studies recognized intracellular copper as a molecular target that can be modulated at the low pH of tumors by polyphenols to mediate prooxidant anticancer activity.

Making sense of the prooxidant action of polyphenols Antioxidants, in general, are believed to counteract the effects of ROS, inhibiting oxidative DNA damage and consequently reducing cancer risk. However, growing evidence suggests that polyphenolic antioxidants can mediate ROS generation, especially in the presence of metal ions; this prooxidant action may serve as the basis for their ability to induce apoptosis in cancer cells (Elbling et al., 2005; Eghbaliferiz and Iranshahi, 2016). Depending on the cellular microenvironment, polyphenolic compounds apparently exhibit either antioxidant or prooxidant activity. In the presence of redox active metals such as copper, they tend to behave as prooxidants, catalyzing the redox cycling of metal ions, which leads to the production of ROS that can damage cellular macromolecules, including DNA (Ahmad et al., 1992; Li and Trush, 1994; Decker, 1997). In contrast to normal human cells, cancerous cells contain elevated copper levels (Gupte and Mumper, 2009), and hence, may be more subject to copper-mediated ROS formation by polyphenols. Therefore, it stands to reason that oxidative DNA breakage induced by polyphenolic compounds in the presence of copper ions may be a crucial mechanism by which cancer cells may die while normal cells survive. Apart from accounting for the observed anticancer properties of polyphenolic compounds, this also provides a plausible explanation for their preferential cytotoxic action toward cancer cells.

Chapter 12 • Prooxidant anticancer activity of plant-derived polyphenolic

It also needs to be emphasized that cancerous cells function with an altered antioxidant defense and as a result, remain under persistent oxidative stress (Pervaiz and Clement, 2004). Evoking further oxidative stress in these cells, beyond a threshold level, can lead to apoptosis induction (Gupte and Mumper, 2009). The modulation of oxidative stress in cancer cells has, in fact, been tried as an approach to sensitize tumors to cytotoxic drugs (Bougnoux et al., 2009). Because cancer cells have a high basal level of ROS owing to a fast rate of growth and metabolism (Kong et al., 2000), a further enhanced exposure to ROS, formed through the mobilization of intracellular copper by polyphenols, can subdue their antioxidant capacity, thereby inflicting irreversible cell damage and apoptosis. On the other hand, normal cells can tolerate such an action of polyphenols better as they carry low basal levels of ROS, as also a normal copper concentration. Therefore, a disparity in the redox status of normal cells and cancer cells may offer a basis for the selective killing of cancer cells by polyphenols.

Conclusion Plant polyphenols are capable of mobilizing and redox cycling nuclear copper, generating ROS in the process that then causes cellular DNA degradation, ultimately leading to cell death. This prooxidant action not only gives new insight into the mechanism of action of plant polyphenols as chemopreventive molecules, but also provides a better explanation for the observed anticancer properties of a variety of polyphenolic compounds with diverse chemical structures. Furthermore, it also renders a basis for exploiting the high copper redox status in cancer cells as a molecular target for devising more effective cancer therapeutic strategies. Finally, in a nutshell, the anticancer properties of polyphenols may be summed up as a combination of their cytotoxic effect on cancer cells (cancersuppressing prooxidant action) and a cytoprotective effect on normal cells (cancerblocking antioxidant action).

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Md. Atiar Rahmana, Md. Rakibul Hassan Bulbula,b, Yearul Kabirc DEPARTMENT OF BIOCHEMISTRY AND MO LECULAR BIOLOGY , UNIVERSITY OF C HI TTAGONG, CHITTAGONG, BANGLADESH b INSTITUTE F OR DEVELOPING SCIENCE AND HEALTH INITIATIVES (I D E S H I ), CE NT R E FOR M E DI C AL BI OT ECHNOL OGY (C MBT) , INSTI TUT E O F P UB LIC HE ALTH BUILDI NG, DHAKA, BANGLADESH c DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, UNIVERSITY OF DHAKA, DHAKA, BANGLADESH

a

Introduction Cancer is a major health concern worldwide. The global demographic status predicts increasing cancer incidence over the next decades, with 420 million new cancer cases annually expected by 2025. According to the data published by GLOBOCAN, 14.1 million new cases and 8.2 million deaths from cancer were estimated in 2012 (Ferlay et al., 2015). Among the several different types, the female breast, colorectal, lung, and prostate cancers are the most commonly diagnosed cancers in Europe (Ferlay et al., 2013). Lung cancer still remains the leading cause of cancer incidences and mortality worldwide (Ferlay et al., 2015). However, the expansion of knowledge for molecular and tumor biology has notably changed cancer treatment paradigms during the past 15 years. Formerly, cancer was categorized and treated completely according to organs of origin or simplistic histomorphologic features. Completely overlapping survival curves are reported in advanced nonsmall-cell lung cancer (NSCLC) patients after the use of four different platinum-based chemotherapy doublets with third-generation drugs (Schiller et al., 2002). Although the trial was limited to lung cancer, it was found that cancer treatment based on a broad use of cytotoxic chemotherapies in unselected patients had reached its therapeutic plateau. Additionally, it became clear that the development of molecular therapies and treatments based on particular molecular alterations was badly needed. Since then, two pillars have driven the subsequent evolution of cancer treatment: acquisition of new technology for tumor molecular profiling and the discovery of predictive molecular targets. These efforts together have led to the two recent revolutions in cancer treatment. The first is genotype-directed precision oncology, which means tailoring personalized therapies to subsets harboring specific genomic abnormalities across different tumor types. The second is targeting components of the tumor microenvironment, in particular the immune system and antitumor immunity.

Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00013-2 © 2020 Elsevier Inc. All rights reserved.

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Despite the numerous existing options to defend against cancer, the eventual success in cancer cures is still lagging far behind due to the huge adverse effects of most of those options. They are, to some extent, unaffordable and intolerable as well. In this context, scientists are moving toward a better alternative with minimum side effects that would be reachable for patients. Currently, plant-based alternative drugs are considered the best alternative due to their minimum adverse effects as well as tolerability and affordability for patients. Plants and plant-based products could be used in different forms such as antioxidants, nutraceuticals, herbals, phytochemicals, and supplements. This chapter discusses the use of plant-derived products, their mechanisms in defending against cancer, and the most prominent compounds currently used as herbals, nutraceuticals, and supplements.

Cancer and oxidative stress The simple way to describe cancer is when cells lose intrinsic control over their growth and division. Some cancers have growths called tumors while others, such as leukemia, do not grow but rather can travel throughout the body using blood circulation or lymph vessels. In 2018, global suffering from cancer increased with an estimated 18.1 million new cases that caused 9.6 million deaths worldwide. Lung cancer was diagnosed as the most prevalent cancer and was responsible for the most cancer deaths, with female breast cancer remaining in second place (Willcox et al., 2004). Regardless of the nature, cancer being inevitably linked with the upstream production of reactive oxygen species (ROS) has been postulated by many researchers. During oxidative stress, ROS predominantly targets DNA molecules and consequently damages the deoxyribose backbone, including the purine and pyrimidine bases (Weinberg and Chandel, 2009) (Fig. 13.1). Oxidative DNA damage alters cellular signaling cascades and is involved in regulating the progression of different types of cancers, including those of the colon, breast, lung, prostate, liver, ovary, and brain (Bray et al., 2018; Lee et al., 2017; Wang et al., 2016). The G ! T transversion is the most observed mutation upon oxidative stress in the p53 suppressor gene (Saed et al., 2017). Due to ROS-mediated DNA damage, the urinary level of 8-OH deoxyguanosine (8-OHdG) is elevated in uterine myomas, breast cancer, lung cancer, and bladder and prostate cancers (Harris and Hollstein, 1993; Matsui et al., 2000; Foksinski et al., 2000). Therefore, urinary 8-OHdG is a biomarker used in early diagnosis for cancer progression (Erhola et al., 1997). Moreover, prolonged ROS production has been linked to somatic mutations and neoplastic transformation, sister chromatid exchanges, genome instability, cell proliferation, rearrangement of DNA sequences, and gene duplications (Wu et al., 2004; Fang et al., 2009). These phenomena lead to the rigorous inactivation of signal transduction, transcription factors, and genes for tumor suppressor p53 and thus contribute to the activation of proto-oncogenes (Visconti and Grieco, 2009). For instance, ROS can attenuate the expression of the DNA mismatch repair genes MutS homologue 2 and 6 and can increase the expression of DNA methyltransferases, guiding the hypermethylation of the genome (Waris and Ahsan, 2006). This leads to promoter silencing of several genes, such as

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ROS at high concentrations Oxidative damage

Lipid Chain breakage Increase in membrane fluidity and permeability

Protein Site-specific amino acid modification Fragmentation of the peptide chain Aggregation of crosslinked reaction products Altered electric charge Enzyme inactivation Increased susceptibility of proteins to proteolysis

DNA Deoxyribose oxidation Strand breakage Removal of nucleotides Modification of bases DNA-protein crosslinks

FIG. 13.1 Reactive oxygen species (ROS)-mediated damage to DNA, proteins, and lipids (Halliwell, 2007).

cyclin-dependent kinase inhibitor-2 (CDKN-2), adenomatous polyposis coli (APC), breast cancer susceptibility gene 1 (BRCA1), murine double minute 2 (MDM2), retinoblastoma protein (Rb), DNA mismatch repair gene, and the human MutL homolog 1 (hMLH1) (Schetter et al., 2010). On the contrary, low or transient levels of ROS can activate cellular proliferation or survival signaling pathways such as the AP1, NF-κB, extracellular signalregulated kinase/mitogen-activated protein kinase (ERK/MAPK), and phosphoinositide 3-kinase/AKT8 virus oncogene cellular homolog (PI3K/Akt). For example, H2O2 can degrade IκBα, the inhibitory subunit of NF-κB (Das and Singal, 2004). Protein kinase C, which participates in several pathways regulating transcription and cell cycle control, is also activated by H2O2 (Das and Singal, 2004). Additionally, ROS induces both the synthesis € ge, and activation of AP-1, a regulator of cellular growth, proliferation, and apoptosis (Dro 2002), and transcription factors such as HIF-1α, STAT3, and p53 (Shaulian and Karin, 2002; Kerr et al., 1992). ROS also can make an epigenetical contribution to cancer development and progression by acting as signaling intermediates downstream of mitogen receptors and € rlach and Kietzmann, 2007). inducers of genetic programs leading to malignancy (Go

Antioxidant therapeutics in cancer Some antioxidants called endogenous antioxidants are produced in our body, and they are used to neutralize free radicals. Endogenous compounds in cells are usually classified as enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH)-dependent enzymes, and nonenzymatic antioxidants, further divided into metabolic and nutrient antioxidants. Metabolic antioxidants belonging to endogenous

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antioxidants such as GSH, lipoic acid, L-arginine, coenzyme Q10, melatonin, uric acid, bilirubin, etc., are produced by the metabolism in the body (Valko et al., 2007; Alexieva et al., 2010). However, the body relies on exogenous sources, primarily dietary sources, to have the rest of the antioxidants it needs. These exogenous antioxidants, including lycopene, beta-carotene, vitamins A, C, and E (alpha-tocopherol), retinol, selenium, riboflavin, zinc, molybdenum, etc., are commonly known as dietary antioxidants. Dietary antioxidants are basically enriched with fruits, vegetables, and grains. Some dietary antioxidants are also available as dietary supplements (Nahum et al., 2001; Fiaschi and Chiarugi, 2012) that modify the cancer initiation and progression pathway, neutralizing the excessive production of ROS within the cells. Antioxidants are often described as “mopping up” free radicals, meaning they neutralize the electrical charge and prevent the free radical from taking electrons from other molecules. Antioxidants either as preventive or therapeutic doses not only defend cancer cells but also decrease chemotherapy-mediated toxicity (Bjelakovic et al., 2014). For example, vitamin E has been documented to reduce chemotherapy-mediated toxicity and, with omega-3 fatty acid, increase the survival time in terminal cancer patients. Vitamin E, other than suppressing free radical-induced progression of lipid peroxidation in normal cells, is also known to induce apoptosis in experimental tumor lines and increase the efficacy of chemotherapy (Lamson and Brignall, 1999). To date, nine randomized controlled clinical trials of dietary antioxidant supplements for cancer prevention have been conducted worldwide for studying the effects of antioxidant supplements in cancer. Most of these natural antioxidant-oriented cancer prevention and therapeutics with extensive preclinical research have become a hot topic in the field of drug discovery throughout the world because they have been shown to inhibit DNA damage, arrest the cell cycle (especially at the G2/M), induce apoptosis, and inhibit angiogenesis in tumor cells (Ayyad et al., 2012). These antioxidant-oriented anticancer drugs are highly demanded because their mechanisms to kill or suppress tumor cells are very precise. Despite this sort of demand, careful identification and validation of novel agents with cellular targets, evaluating efficacy, ensuring safety and toxicity, confirming metabolism and bioavailability with robust epidemiological studies (Ahmad and Mukhtar, 2013) are predominantly needed for a sustainable cancer therapeutic setting.

Phytochemicals as anticancer therapeutics Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without hampering normal cells. Phytochemicals are pleiotropic in their function and target multiple signaling events; hence they are the most suitable candidate for anticancer drug development. >3000 plant species have been reported to be used in the treatment of cancer (Hartwell, 1982). Reports on natural products for cancer prevention showed an availability of >3000 anticancer drugs. Out of 121 prescription drugs for cancer treatment, 90 being used today are plant-based (Shishodia and Aggarwal, 2004). Almost 74% of them were discovered from folklore claims (Shishodia and Aggarwal, 2004).

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Thirty-five percent of traditionally used anticancer plants have been evaluated through in vitro screening and found good activity against various cancer cell lines (Tariq et al., 2017). In 2017 alone, 16 new drugs got approval from the US Food and Drug Administration (FDA) in the field of oncology alone while the European Medicines Agency (EMA) accepted 48 cancer drugs for 68 indications during 2009–2013 (Habtemariam and Lentini, 2018). The anticancer property of plant polyphenols is due to their structural similarity with chemopreventive drugs that can regulate ontogenesis expression and the carcinogen metabolism. Major phytometabolites and polyphenolics such as alkaloids, flavonoids, phenolics, tannins, glycosides, gums, resins, and oils are considered to show anticancer potential, either in their natural or altered forms (Singh et al., 2013). The most remarkable phytochemicals include vinblastine, vincristine, taxol, boswellic acid, elliptinium, etoposide, colchicinamide, 10-hydroxycamptothecin, cucurbitacin, quercetin, catechin, curcumol, gossypol, ipomeanol, lycobetaine, tetrandrine, homoharringtonine, thymol, carvacrol, kaempferol, 1 and 1,8-cineole, α-pinene, myrcene, β-sitosterol monocrotaline, umbelliprenin, curdione, and indirubin. These have been isolated and identified from a vast group of plants, especially Achillea wilhelmsii, Allium sativum L, Ammi majus, Ammi visnaga, Artemisia absinthium L, Astragalus cytosus, Avicennia marina, Boswellia serrata, Camellia sinensis, Citrullus colocynthis, Saffron (Crocus sativus L), Curcuma longa, Ferula assa-foetida, Glycyrrhiza glabra, Lagenaria siceraria Standl, Medicago sativa L, Mentha pulegium, Nigella sativa, Peganum harmala L, Physalis alkekengi, Polygonum aviculare, Rosa damascenes Mill, Silybum marianum, Taxus baccata L, Thymbra spicata, Thymus vulgaris, Trigonella foenum-graecum L, Urtica dioica L, Vinca rosea, Zingiber officinale, and Withania somnifera (Kooti et al., 2017; Zeng et al., 2017). A number of the plants and plant-derived products studied and found to be effective against different types of cancerous conditions are summarized in Table 13.1.

Cellular mechanism of actions of phytochemicals The exact mechanism of phytochemicals to perform anticancer functions is still unclear. They exert a wide and complex range of actions on the nuclear and cytosolic factors of a cancer cell. They can maintain an ROS/RNS homeostasis in a cellular system, absorbing the ROS or promoting the activities of antioxidant enzymes (e.g., superoxide dismutase, glutathione, and catalase) in a transformed cell, which has partially pointed in the introduction section. But the existing hypothesis delineates that a phytomolecule may suppress the malignant transformation of an initiated preneoplastic cell or it may block the procarcinogen metabolic conversion (Seo et al., 2015). The cellular signaling events involved in the growth, invasion, and metastasis of cancer cells could also be modulated by the phytomolecule. For example, ellagic acid of the pomegranate induces apoptosis in prostate and breast cancer cells, and inhibits the metastasis processes of various cancer types. Epigallocatechin gallate (EGCG), an anticancer phytomolecule, suppresses the ornithine decarboxylase activity and the enzyme becomes dysfunctional to signal the cell

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Table 13.1 Clinical use of plant-derived drugs/products exhibiting anticancer activities (Yin et al., 2013). Plant-derived products For breast cancer Isoflavone Isoflavones genistein and daidzein Alkaloids Coumarins Flavonoids and polyphenols Terpenoids Quinone Artemisunate For prostate cancer Vitamin E Epigallocatechin-3-gallate (EGCG)

Baicalein

Lycopenes

PC-SPES

Wedelia chinensis (Asteraceae) For lung cancer Platycodon grandiflorum (Campanulaceae) Morus alba (Moraceae) Prunus armeniaca (Rosaceae) Rhus verniciflua (Anacardiaceae) Perilla frutescens (Labiatae) Stemona japonica (Stemonaceae) Tussilago farfara (Compositae) Draba nemorosa (Brassicaceae) For liver fibrosis and cancer Inchin-ko-to (TJ-135) Yi Guan Jian (YGJ) Yi Guan Jian (YGJ) Salvianolic acid B

Suppressive effects on carcinogenesis and cancer metastasis To reduce risk of breast cancer To confer weak estrogenic effects Inhibition of cancer cell growth Inhibition of cancer cell growth Antiproliferation MCF-7 cell apoptosis To induce G2-M arrest and autophagy by inhibiting the AKT/mammalian target of the rapamycin pathway in breast cancer cells Decreases the proliferation of human breast cancer cells from expressing a high ERα: ERβ ratio Reduces the risk of lethal or advanced prostate cancer relative to nonusers Arrests LNCaP and DU145 prostate cancer cells at the G0-G1 phase of the cell cycle Inhibit metalloproteinase in vitro Chemopreventive activities Impairs the proliferation of androgen-independent PC-3 and DU145 prostate cancer cells in culture Induces cell-cycle arrest at the G0-G1 phase Induces apoptosis of prostate cancer cells at concentrations achievable in humans Suppresses the expression of a specific androgen receptor in prostate cancer Decreases prostate cancer risk Diminishes oxidative damage in lymphocytes Significantly decreases levels of PSA and less oxidative damage Decreases serum testosterone concentrations (P < 0.05); decreases serum concentrations of prostate-specific antigen Antitumor efficacy against cancer cell lines Inhibits the androgen receptor (AR) signaling pathway Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Anticancer effect in lung cancer patients Preventive effect on liver fibrosis

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Table 13.1 Clinical use of plant-derived drugs/products exhibiting anticancer activities (Yin et al., 2013)—cont’d Plant-derived products

Suppressive effects on carcinogenesis and cancer metastasis

Curcumin Compound 861 Sho saiko-to (TJ-9) For pancreatic cancer GDC-0449, IPI-926, XL-139, and PF-04449913 Cyclopamine

Suppressive effect on hepatic fibrogenesis and carcinogenesis Suppressive effect on hepatic fibrogenesis Reduces/limits the progression of hepatocellular carcinoma SMO antagonists; deregulation of sonic hedgehog homology (SHH) Inhibit SHH signaling by directly binding to the 7-helix bundle of the SMO protein; arrest the growth of pancreatic tumors Weakens the recruitment of BMPCs into cancer cells and reduces the formation of tumor vasculature The cancerous vascular system becomes unstable after treatment with cyclopamine due to the expression of angiopoietin-1

to proliferate faster and bypass apoptosis. Luteolin, a flavonoid molecule, obstructs epithelial mesenchymal transition. Flavanones, isoflavones, and lignans prevent estrogen binding to the cancer cells and decrease their proliferation. Curcumin, bilberries anthocyanins, EGCG, quercetin, and caffeic acid and its derivatives act by controlling the central inflammatory signaling pathways. Besides these mechanisms, anticancer phytomolecules also target several other signaling pathways/molecules to reduce the growth and metastasis of cancer cells (Vareed et al., 2008; Seo et al., 2015). Epigenetic modifications such as changes in DNA methylation and the chromatin acetylation pattern can lead to uncontrolled cellular proliferation. Inhibitors to the DNA methylation process as well as histone acetyltransferases (HAT) and deacetylases (HDAC) could be effective tools to treat cancer. Glabridin uses the JNK1/2 pathway for apoptosis in oral cancer cells (Chen et al., 2018). Apigenin, the flavone found in parsley, celery, and chamomile, targets the leptin/leptin receptor pathway and induces apoptosis in lung adenocarcinoma cells (Cincin et al., 2018). Caffeic acid, chrysin, ɑ-coumaric acid, and ferulic acid induce a proline dehydrogenase/proline oxidase-dependent apoptosis in human tongue squamous cell carcinoma (Yang et al., 2018). In breast cancer cells, rosmarinic acid reduces DNA methyl transferase activity and interferes with RANKL/RANK/OPG networks; it also targets the PKA/CREB/ MITF pathway. Calcitriol inhibits prostaglandins as well as COX-2 and VEGF signaling while preventing the angiogenesis of cancer cells (Dı´az et al., 2015). Colchicine upregulates the dual specificity phosphatase 1 (DUSP1) gene in gastric carcinogenesis (Lin et al., 2016), which also prevents the growth of hepatocellular carcinoma cells through upregulation of the A-kinase anchoring protein 12 (AKAP12) and transforming growth factor beta-2 (TGF-β2) proteins (Kuo et al., 2015). Autophagy-directed apoptosis is another common scenario in cancer cells. The abnormal metabolic demand promotes autophagy to apoptosis or cell cycle arrest. Flavonoids follow an autophagy survival mechanism or the autophagy apoptosis decision to eradicate

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cancer (Fan and Zong, 2013). For example, kaempferol induces autophagy in human lung cancer cells via the IRE-JNK-CHOP pathway (Kim et al., 2018); silibinin upregulates the beclin-1 and Atg12-Atg5 formation to induce MCF7 breast cancer cell death; and the flavone isoorientin induces autophagy in hepatoblastoma cancer and activates apoptosis by the JNK, PI3K/Akt, and p38MAPK signaling pathways (Khan et al., 2012; Yuan et al., 2014). Mitochondrial dysfunction due to calcium overload induces apoptotic tumor cell death (Lee et al., 2016). Some flavonoids induce paraptosis in cancer cells. For example, the plant polyphenol xanthohumol via the p38MAPK pathway induces paraptosis in leukemia cells (Mi et al., 2017) while hesperidin causes paraptosis in HepG2 cells (Yumnam et al., 2016). Flavonoids can prevent malignancy by restricting epithelial mesenchymal transition (EMT) and induce cell cycle arrest in many cancers. Nobiletin, a hexamethoxyflavone, inhibits the EMT process initiated by hypoxia through the NF-ĸB and the Wnt/β-signaling pathways in renal cell carcinoma (Liu et al., 2018). The chalconoid cardamonin induces apoptosis and cell cycle arrest in breast cancer by dampening Wnt3a/β-catenin-mediated EMT and reduces the metastatic signal (Shrivastava et al., 2017). A mechanism involved with the initiation and progression of different types of cancer genes is shown in Fig. 13.2.

Gingerol

Oroxylin, Vitamin E Tocopherols

Tocotrinols

Cyanidin

Fisetin

COX-I and II MMP-2 and 9 COX-II ErK, JNK, TNF alpha,

PI3K/Akt mTOR

Curcumin

Bcl-2, mTOR, p65, Akt, Bcl-xL, pRB, EGFR, NF-kB, Cyclin DI STAT3

Flavopiridol

Topoisomerase-I COX-I

Chrysin Silamarin Resveratrol

GI, G2, M phase arrest Cdc2, CDK2, CDK4 inhibitiob GI, G2, M phase arrest

Kaempferol

Reduces the level of; MMP-9, NFkB, Bcl-2, Cytokines NFkB, Topoisomerase-II PI3K, AKt, MAPK/ERK, MMP, Bcl-2

Resveratrol

Apigenin

Ursolic acid

Genistein

Sre kinase, iNOS COX-II, NFkB

Denbinobin

FIG. 13.2 Effect of phytochemicals with anticancer properties on gene activation in order to block cancer initiation and progression (Rahmani et al., 2014). From Iqbal, J., Abbasi, B.A., Mahmood, T., Kanwal, S., Ali, B., Shah, S.A., Khalil, A.T., 2017. Plant-derived anticancer agents: a green anticancer approach. Asian Pac. J. Trop. Biomed. 7, 1129–1150. © 2017 Hainan Medical University.

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Cephalotaxus, an alkaloidal phytochemical used against a wide range of cancer including A-549 lung cancer, HeLa, SGC-7901 gastric cancer cell lines through inhibiting protein synthesis (Feldman et al., 1996). Homoharringtonine, a cephalotaxine alkaloid, has been used in the treatment of chronic myeloid leukemia in patients with resistance and/or intolerance to two or more tyrosine kinase inhibitors after FDA approval in 2012 (Feldman et al., 1996). Genistein is an isoflavone and has a proapoptotic function against colorectal cancer (Mizushina et al., 2013). The flavone fisetin is available in strawberries, apples, grapes, and onions. Fisetin holds cancer migration and proliferation while inducing apoptosis in human colon cancer. Vinca alkaloids (VA) involve disarraying microtubular association or cell cycle arrest at the metaphase (Moudi et al., 2013). Cyanidin glycosides, that is, Cyanidin-3-orutinoside, cyanidin-3-O-glucoside, and Oroxylin A, are plant-derived phytochemicals that suppress iNOS and COX-2 gene expression in colon cancer cells (Kim et al., 2010, Chen et al., 2000). Again, Oroxylin A and 5-FU are used in a combinatorial therapy in colorectal cancer to minimize the side effects of 5-FU (Kenny et al., 2015). One important thing needs to be addressed thoroughly to maximize the efficiency of plant-derived anticancer drugs. Structure modifications, combinatorial chemotherapy, and changes in the physical states of formulation for drug delivery can increase the clinical application of respective drugs. For example, Paclitaxel has a strong antitumor effect but also has serious side effects, including hypersensitivity reactions, drug resistance, and cell toxicity. Paclitaxel (PTX) and etoposide (ETP) loaded with lipid nanoemulsions (LDE) increased the anticancer properties with less toxicity in melanoma-bearing mice compared to PTX + ETP (Kretzer et al., 2012). In prostate cancer, the GM-CSF surface-modified tumor-cell vaccine showed much better clinical outcomes with a paclitaxel combination (Isonishi et al., 2013). Combinatorial therapy with docetaxel, paclitaxel, and carboplatin had greater results in patients of advanced ovarian cancer than a single kind of agent (Isonishi et al., 2013). Docetaxel induces excessive expression of drug-resistant genes (ABCA4 and ABCA12) in MCF-7 breast cancer cells. However, the dilemma can be solved by using both docetaxel and curcumin in combination (Aung et al., 2017).

Nutraceuticals as anticancer therapy A new term was coined between nutrients and pharmaceuticals called nutraceuticals. Dr. Stephen DeFelice first coined the term in 1989, defining nutraceuticals as “foods, food ingredients, or dietary supplements that demonstrate specific health or medical benefits, including the prevention and treatment of disease beyond basic nutritional functions” (Kalra, 2003; Schmitt and Ferro, 2013). Many of our daily food or food constituents are full of polyphenols that may have antitumor potential. Garlic, soya bean, ginger, tea, honey, propolis, and others might have chemopreventive activities. Curcumin, an inevitable part of our daily foodstuff, is the most studied polyphenol, and the PubMed database contains 9500 publications relating to this compound with 1100 reviews. This compound displays marked anticancer effects, and it is well known that the consumption of a

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curcumin-rich diet is inversely correlated with several human cancer types. Dietary berries containing a number of polyphenols are shown to have anticancer effects due to the presence of anthocyanidins as well as the sugar-free counterparts of anthocyanins, including aurantinidin, capensinidin, cyanidin, delphinidin, europinidin, hirsutidin, malvidin, pelargonidin, peonidin, petunidin, pulchellidin, and rosinidin, that impair most of the biological processes involved in cancer aggressiveness. Green tea is one of the most extensively consumed beverages in the world (along with coffee). Most of the anticancer effects of green tea are related to EGCG (mentioned earlier). Capsaicin, the chief pungent component in the fruits of Capsicum, is involved in the capsaicin-induced proapoptotic effects in cancer cell lines that are sensitive to proapoptotic stimuli (Lefanc et al., 2017). Numerous nutraceuticals such as caffeic acid (alkaloid) originated from a large number of plants including burdock, hawthorn, artichoke, pear, basil, thyme, oregano, apple, etc. Caffeic acid derivatives also exist in honeybee propolis, fisetin (flavonoid) from onions, cucumbers, apples, persimmons, strawberries, etc.; Ferulic acid (polyphenol) from oats, rice, artichokes, oranges, pineapples, apples, peanuts, etc.; Lycopene (carotenoid) from red fruits (including tomatoes), grapefruit, watermelons, and many vegetables; Naringenin (flavonoid) from grapefruits, oranges, tomatoes (skin), water mints, etc.; Sulforaphane (organosulfur) from cruciferous vegetables (broccoli, Brussel sprouts, cabbages, cauliflowers, mustards, radishes, watercress, turnips, etc.); piperine (alkaloid) from black pepper (Piper nigrum); Cinnamic acid (polyphenol) from cinnamon oil and honeybee propolis; Diallyl disulfide (organosulfur) from garlic; and gallic acid (polyphenol) from green tea, the Caribbean tropical tree Pimenta dioica (for spicy food), grapes, berries, etc. Their antitumor effects in many cases are proven. In some other cases, it is under review as to whether nutraceuticals minimize cancerous events or inhibit cancer cell growth, depending on the nature of the nutraceuticals available (Fig. 13.3). However, with our increased learning and understanding of biology and chemistry, nutraceutical research is expected to be shifted more into the area of chemoprevention (Ranzato et al., 2014). Organic acids could be inflammatory mediators with antioxidant, hepatoprotective, and chemopreventive properties (Friedel et al., 2009). Some polysaccharides such as mushrooms are immune-boosting chemopreventive polysaccharides (Sun et al., 2016; Friedel et al., 2009) while some others such as fibrous polysaccharides bind carcinogens, lower bile acids, and modulate the estrogen metabolism (Buckingham et al., 2010). Polysaccharides from the traditional Chinese medicine (TCM) adaptogen increase the whole blood natural killer cell (NKC) concentration via granzyme regulation and perforin expression, leading to increased NKC cytotoxicity and decreased adverse effects from radiation therapy (Buckingham et al., 2010). Perforin forms pores in target cells, allowing serine protease granzyme to diffuse into target cells and initiate apoptosis. Organosulfur compounds comprised of indoles, thiosulfonates, and isothiocyanates are commonly derived from cruciferous vegetables. There are various lipid subgroups, including fats, waxes, phospholipids, glycolipids, and polyprenyl compounds. Fat-soluble vitamins, steroids, and isoprenoids (terpenoids) are polyprenyl compounds. Many of these fatty acids are involved in anticancer activity. Isoprenoids improve receptor functionality and enhance antioxidative power (Rais et al.,

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Tumor spread

Inhibits tumor invasion Antimetastasis

Tumor growth

Precancerous lesions

Pathways influenced by nutraceuticals

Activates anti-inflammatory modulators Induce phase II enzymes Inactivate phase I enzymes Chemopreventive

Inhibits cell proliferation Induce cell differentiation Induce apoptosis Chemotherapeutic

FIG. 13.3 Cellular pathways affected by the activities of bioactive components in dietary sources. Of the natural compounds present in dietary sources, some are more involved in regulating chemopreventive pathways and some are more effective in influencing chemotherapeutic pathways (Grattan Jr, 2013).

2016). A floral essential oil (Farnesol) and geranium, citronella, lemon, palmarosa, and rose oils (geraniol) have in vivo cytotoxicity against leukemia, murine liver cancer, and melanoma (Cline and Hughes, 1998). Omega-3-PUFAs form resolvins and protectins and suppress IL-β, COX-2, and TNF-α. They also bind peroxisome proliferator receptor activator (PPAR) gamma, allowing omega-3-PUFAs to induce cancer cell apoptosis and inhibit cell proliferation (Cline and Hughes, 1998). Coumarin was found to reduce melanoma recurrence and inhibit renal-cell carcinoma in clinical trials (Varker et al., 2012). Coumarin has dose-dependent cytotoxicity against the Hep2 cell line (Wang et al., 2013). Carbon-4-substituted coumarin was antiproliferative against breast and liver carcinomas while inhibiting aromatase, protein kinase, sulphatase, 17β-HSD3, Hsp90, DNA intercalation, Cdc25, HDACs, NF-κβ, microtubulin, and TNF-α (Wang et al., 2013). A synthetic coumarin with a 4-position methylene thiol linker to a 6-membered heteroaromatic ring (4-Hydrazinyl-2-{[(6-methyl-2-oxo-2Hchromen-4-yl)methyl]sulfanyl}-6-phenylpyrimidine-5-carbonitrile) is cytotoxic to HepG2 hepatocarcinoma cells and MCF-7 breast cancer cells extrapolated with IC50 of 4 μg/mL (Morsy et al., 2017). Ferula narthex Bioss (an Ayurvedic spice called “Raw”) derived sesquiterpene (C15H24) from the chloroform soluble part has been found to be active against PC3 cells (Dandriyal et al., 2016).

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Flavonol dihydrokaempferol rhizomes, isolated from the roots of Smilax bockii and from S. glabra, are used in traditional Chinese medicine (Goulas et al., 2016). The flavonol (2R,3R)-dihydrokaempferol-3-O-β-D-glucopyranoside from the leaves of S. glycyphylla and dihydrokaempferol-3-O-α-L-rhamnoside from S. china were less apoptotic to MDA-MB-231 and MCF-7 than oxyresveratrol and resveratrol (Goulas et al., 2016). Taxifolin (dihydroquercetin) is a constituent of milk thistle seed silymarin extract and the S. glabra rhizome, (Goulas et al., 2016) and taxifolin-3-O-glycoside is cytotoxic like dihydrokaempferol and dihydrokaempferol-3-O-α-L-rhamnoside, although taxifolin is weakly cytotoxic (Goulas et al., 2016). Out of numerous flavanones, hesperetin and naringenin undergo transformation by neohesperidose and rutinose, becoming the flavanone glycosides hesperidin, neohesperidin, narirutin, and naringin; hesperetin is apoptotic to A431 epidermoid skin carcinoma (Rau´l et al., 2017). Naringenin, a natural flavanone found in oranges, grapefruits, and tomato skins, is effective against in vivo HepG2 cells and A431 and B16-F10 melanoma cells. Naringenin induces mitochondrial apoptosis via Bcl-2, Bax, caspase-3, and p53 (Korbakis and Scorilas, 2012; Rau´l et al., 2017). It modulates PCNA, CYP1A1, and NF-κβ. Hesperidin is more cytotoxic than naringin and neohesperidin against HepG2, and is also antiproliferative and apoptotic against A549 lung cancer ´ l et al., 2017). Hesperidin actiand NCI-H358 nonsmall cell lung cancer (NSCLC) cells (Rau vates MMPs, Erk, ROS production, mitochondrial calcium overload, and membrane potential loss while modulating NF-κβ pathways and fibroblast growth factor. Naringin also likely activates caspase-8 and caspase-9 (Rau´l et al., 2017). The flavones polymethoxyflavones (PMF) are unique to citrus peels, and are thus used in TCM (Kuete et al., 2016). Tangeretin, a tangerine-derived PMF, is anti-inflammatory in microglial cells, and induces G1 arrest or apoptosis in cancer cells (Kuete et al., 2016). Another PMF, tangeretin, is antiproliferative to A549, MDA-MB-435 breast cancer, MCF-7, HT-29 colon cancer, and HL-60 leukemia cell lines (Alzaharna et al., 2017; Isono et al., 2018). The tangeretin derivative 5-AcTMF is reported as antiproliferative to the U226 myeloma, MCF-7, and CL1–5 NSCLC cell lines (Rau´l et al., 2017). Some common cell lines used for different types of cancer studies and diagnoses are summarized in Table 13.2. Lignans are also phytoestrogens that are derived from berries, flaxseed, sesame seeds, and whole grains (Kuete et al., 2016). Matairesinol and secoisolariciresinol function as weak estrogen agonists; they elevate SHBG and inhibit aromatase (Buckingham et al., 2010). Thymoquinone and dithymoquinone are derived from the Nigella sativa L. seed (blackseed). Thymoquinone and dithymoquinone displayed in vivo cytotoxicity to multidrug-resistant cells (Li et al., 2013). Thymoquinone has cytotoxic activity against MCF-7/Doxorubicin via p53, PTEN, and p21 upregulation; PI3K-Akt, NF-κβ, PPAR, and phase I enzyme inhibition; and phase II enzyme (GST and N-acetyl transferase) activation (Li et al., 2013). Thymoquinone activates caspace-3, -8, and -9 against HL60 p53myeloid leukemia, whereas it induces Caspace-3 apoptosis against Hep-2 cells (Paterni et al., 2013). It inhibits COX2, which affects lung, breast, stomach, and pancreatic cancers (Paterni et al., 2013). Thymoquinone is also active against bladder, bone, colon, and skin cancers (Paterni et al., 2013). Stilbenes such as resveratrol (a berry-, grape-, and

Chapter 13 • Plant-based products in cancer prevention and treatment

Table 13.2 lines.

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Cytotoxic plants used for phytochemical preparation toward cancer cell

Plant

Cancer cell line(s)

Abelia triflora (leaf) Abutilon indicum (leaf) Amphipterygium adstringens (bark) Annona crassiflora and A. coriacea (leaf and seed)

A549 A549 OVCAR3 (ovary adenocarcinoma) UA251 (glioma), UACC62 (lymphoid melanoma), MCF7, NCIH460 (lung cancer), 786-0 (renal carcinoma), HT29, NCIADR-RES (ovary cancer), OVCAR, K562 (myeloid leukemia) M12.C3F6 (B-cell lymphoma), RAW264.7 (leukemia) HeLa MCF-7 HCT116

Argemone gracilenta Camellia sinensis (black tea) Catharanthus roseus Emblica officinalis (fruit) Centaurea kilaea Chamaecyparis obtuse (leaf) Chresta sphaerocephala (leaf and stem) Cichorium intybus Croton sphaerogynus (leaf) Curcuma longa (rhizome) Elaeocarpus serratus (leaf) Fraxinus micrantha Harpephyllum caffrum (leaf) Holarrhena floribunda (leaf) Ipomoea quamoclit (leaf) Ipomoea pestigridis (leaf) Justicia tranquibariensis (roots) Nardostachys jatamansi (roots and rhizome) Piper cubeba (seed) Piper pellucidum (leaf) Premna odorata (bark) Psidium guajava (leaf) Robinia pseudoacacia Rubus fairholmianus (root) Sansevieria liberica (root) Sideritis syriaca (leaf) Solanum nigrum Theobroma cacao (leaf) Trapa acornis (shell) Tridax procumbens Triumfetta welwitschii Vernonia amygdalina (leaf) Vinca major (aerial parts)

MCF7, HeLa, PC3 HCT116 OVCAR3, 786-0, U251 MCF7 U251, MCF7, NCIH460 A549 MCF7 MCF7 HCT116, A549, MCF7, HepG2 MCF7 HT29 HeLa CNE1 (nasopharynx carcinoma), HT29, MCF7, HeLa HepG2 HeLa MCF7, MDA-MB-231 MCF7, MDA-MB-468 HeLa HCT116, MCF7, A549, AA8 EAC, HeLa, MDA-MB-231, MG-263 C6 (glioma), MCF, T47D (breast cancer), A549 Caco2 HeLa, HCT116, THP1, (leukemia) MCF7 HeLa SiHa (cervix carcinoma) C33A (cervix carcinoma) MCF7 SKBR3 (breast cancer), MDA-MB-435 A549, HepG2 Jurkat T cells (T-cell leukemia) HL60, SMMC7721, A549, MCF7, SW480 (colorectal adenocarcinoma) HEp-2 (HeLa derived)

This table is cited from Singh et al. (2016) and individual references within the table have been avoided.

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peanut-derived polyphenol with stilbene derivatives) upregulate the cancer cell line wildtype p53 (Kuete et al., 2016). Rhapoantigenin (stilbene derivative of resveratrol) degrades HIF-1α (thereby suppressing MAPK and VEGF); it has shown a greater antiangiogensis effect than resveratrol (Kuete et al., 2016; Wang et al., 2012). Corilagin, an antitumor herbal medicine isolated from Phyllanthus niruri L, is apoptotic to Hey, SKOv3ip, and HO-8910 PM ovarian cancer cell lines by inducing G2/M phase arrest and TGF-β/Akt/Erk/Smad modulation (Rahmani et al., 2014). Pomegranate, containing the aromatase gene, produces punicalagin, which is metabolized to ellagic acid that, in addition to total pomegranate tannin, is apoptotic to HT-29 cells (Rahmani et al., 2014). Punicalagin and total pomegranate tannin inhibit NF-κβ response element binding and TNF-α mediated COX-2 expression (Chen et al., 2012; Manivannan et al., 2019) Punicalagin also triggers autophagy cell death in U87MG cells by increasing AMPK-p27 (Chen et al., 2012, Manivannan et al., 2019). Litchi contains proanthocyanidins A1, A2, and A6, and procyanidins B2 and B4 (Rahmani et al., 2014), which are polymeric tannins that are depolymerized to anthocyanidins. Xanthones: Pericarps of Garcinia mangostana (Mangosteen Linn fruit) contain gartanin and α-Mangostin, which has anticancer and chemosensitizing activity to pancreatic cancer and melanoma cells (Panth et al., 2017). α-Mangostin via ROS-mediated apoptosis induction showed dose-dependent anticancer activity against A549 cells, but these effects are negated by N-acetyl cysteine. α-Mangostin increases the Bax/Bcl-2 ratio dose-dependently, inhibits A549 cell migration, and downregulates the A549 antioxidants–glutathione peroxidase, catalase, and GSH (Panth et al., 2017). Phytic acids include defatted rice bran phytate and inositols, including inositol phosphates, inositol hexakisphosphate (InsP6), and myo-inositol (Luo et al., 2017). Usually, the cereals, legumes, and oilseeds yield InsP6, which is broken down to myo-inositol and inositol phosphates (Luo et al., 2017). Inositols inhibit cell cycles by opposing pRB phosphorylation and increasing pRB/E2F complex formation (Luo et al., 2017). Inositols reduce PI3K, downregulate Akt and Erk, disrupt FGF receptor binding and EGF-transduction, inhibit NF-κβ, and decrease COX2 and PGE2 expression (Luo et al., 2017). Inositols impair β-catenin translocation, Notch-1, SNAI1 release, N-cadherin, and Wnt-activation (Luo et al., 2017). Inositols decrease cofilin and fascin, inhibit MMP and ROCK1/2 release, and upregulate focal adhesion kinase (FAK) and e-cadherin, impairing invasiveness and contributing to cancer microenvironment alterations (Luo et al., 2017). A number of phytosterols from nuts, lettuce, capers, cucumbers, flaxseed, and rice bran are involved in cancer prevention. β- Sitosterol, a phytosterol, does not stimulate the endometrium, nor do plant stanols and stanol esters stimulate ER-positive MCF-7. β-Sitosterol, which may be most biologically active with liposomal delivery, downregulates the NF-κβ, thereby sensitizing cancer cells to TNF-α-induced apoptosis (Zhang et al., 2018). β-Sitosterol reduces MDA-MB-231 triple negative breast cancer (TNBC) and MCF-7 tumors and activity against MDA-MB-231 is significant as although TNBC comprises only 15% of breast cancer, TNBC is treatment resistant, being unresponsive to endocrine and other targeted treatments (Bizzarri et al., 2016). β-Sitosterol and lupeol are the main anticancer constituents of Nardostachys jatamansi DC, a traditional Himalayan medicinal herb used for cancer treatment (Grattan Jr, 2013).

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Saponins, polycyclic aglycons of plant foods, are cell proliferation regulators and immune modulators (Friedel et al., 2009; Buckingham et al., 2010). Betulinic acid from the Betula alba (birch) bark, a plant triterpenoid saponin, has known chemopreventive, antiinflammatory, antiviral, and antioxidant properties (Wu et al., 2016). Betulinic acid increases TNF-α, IL-2, and CD4+ lymphocyte subsets. Betulinic acid increases the CD4+:CD8+ ratio in a dose-dependent manner. Betulinic acid decreases the B-cell lymphoma 2 (Bcl-2) protein and cell proliferation marker (Ki-67) protein expression and increases caspase-8 protein expression (Chaudhary et al., 2015). Different types of terpenes as nutraceuticals do contribute to cancer therapy. Triterpene, the major active component of Trypterigium wilfordii (thunder duke vine), should be antiangiogenic and cytotoxic due to the modulation of MMP-9, the intercellular adhesion molecule (ICAM)-1, the cell survival inhibitor of the apoptosis protein (IAP)-1, X-linked (X)-IAP, Bcl-xL, Bcl-2, flice inhibitory protein (cFLIP), survivin, and cell proliferation molecules (cyclin D1, COX-2) in tumor cells (Kuete et al., 2016). Monoterpenoids: Monoterpenoids induce apoptosis, cell differentiation, and phase I and II detoxification enzymes, including GST, while also affecting cellular energy and inhibiting cell proliferation (Friedel et al., 2009). Monoterpenoids include limonene found in cardamom and Perillyl alcohol derived from the essential oils of lavandin, spearmint, peppermint, cherries, and celery seeds. Ferula species-derived umbelliprenin inhibits MMPs, but only has greater antitumor activity than cisplatin against M4Beu melanoma. It is ineffective against A549, DLD-1, MCF-7, PA1 paclitaxel-sensitive ovarian cancer, and PC3 prostate cancer cell lines (Ahmad et al., 2015). Similarly, F. gummosa-derived sesquiterpene coumarin feselol has antitumor activity against U937 but not the MCF-7, M14, A549, Saos-2, T98G, or FRO cell lines (Ahmad et al., 2015). Diterpenoids: In gallbladder cancer, the diterpenoid oridonin derived from antiangiogenic Rabdosia rubescens activates caspase-3 and 9 mitochondrial pathway apoptosis, activates PARP1 cleavage, increases the Bax/Bcl-2 ratio, and inhibits NF-κβ nuclear translocation (Ahmad et al., 2015). In acute lymphoblastic leukemia, oridonin inhibits the AktmTOR and Raf-MEK-Erk pathways, but in in vitro human osteosarcoma cells shows Akt and MAPK inhibition (Bizzarri et al., 2016). Oridonin-treated murine L929 fibrosarcoma cells indicate Erk-p53 activation leading to G2/M phase cell cycle arrest (Bizzarri et al., 2016). Tetraterpenes: Carotenoids are antioxidant tetraterpenes (Friedel et al., 2009). β-Carotene found in apricots, pumpkins, carrots, and sweet potatoes is also antiproliferative and antiangiogenic, while inducing cellular differentiation (Buckingham et al., 2010).

Therapeutic efficacy and purification of anticancer phytochemicals The therapeutic potential and efficacy of medicinal plants usually depend on the nature and quality of active phytochemicals, their quantity, the climate where they mature, the season when they grow, and the soil nutrients the plant takes up. Even the various parts of plants show different extents of phytopharmacological effects. Importantly, the issue that

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guides the function of plant-derived products more is their additive or synergistic effects rather than their purity. However, these phytochemicals are developed into active anticancer drugs through sequential purification processes such as isolation and assay of the phytochemicals, their combinatorial chemistry, and bioassay-guided fractionation. Bioassayguided fractionation involves bioactive phytochemical separation from a mixture of compounds using analytic techniques and biological screening procedures. The common approach is to begin with the extraction of crude followed by bioactivity testing. Antioxidative effects of the natural crude extracts or fractions are assayed by using in vitro measures such as the 2,2-diphenyl-1-picryl-hydrazyl scavenging assay, the Ferric reducing assay, the superoxide scavenging assay, the nitric oxide assay, the hydroxyl radical scavenging assay, etc. The active extract is further fractionated using either column chromatography or other suitable matrices. Eluted fractions are tested for bioactivity and active fractions are examined by various analytic techniques such as thin layer chromatography (TLC), HPLC, FTIR, and mass spectroscopy (MS) (Fig. 13.4). To purify compounds, solvents should be used in an increasing polarity order. Sephadex, silica, superdex, or any other suitable matrix can be used for fractionation. Vanilline-sulfuric acid can be used as a dyeing reagent for the detection of natural compounds. Once the compounds are purified, molecule(s) must be examined through cell line and in vivo experiments for anticancer effects. When a molecule is confirmed to have a strong antitumor effect, other issues such as safety and adverse effects, dose pharmacokinetics, concentration, drug interactions, etc., must be explored for the drug molecule (Singh et al., 2016).

FIG. 13.4 Development of bioactive phytomolecule(s) in an anticancer product (Singh et al., 2016).

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Development and use of synthetic analogs to plant-derived substances The development of novel plant-derived natural products and their analogs for anticancer activity details efforts to synthesize new derivatives based on bioactivity and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification. There are various classes of recently discovered compounds that possess potent antitumor activity. These compounds were obtained by bioactivity and mechanism of action-directed isolation and characterization, coupled with rational drug design-based modification and analog synthesis. Among the nine anticancer plant-derived compounds approved since 1961, etoposide has been modified to its thiophene analog teniposide (2), which is used clinically to treat small cell lung cancer, testicular cancer, leukemias, lymphomas, and other cancers. Another natural anticancer drug called podophyllotoxin, which is a bioactive component of Podophyllum peltatum, P. emodi, and P. pleianthum, has been modified to several series of 4-alkylamino and 4-arylamino epipodophyllotoxin analogs; all have been found to be excitingly cytotoxic to etoposide-resistant cell lines. Another natural anticancer drug and topoisomerase I inhibitor called camptothecin, a natural alkaloid isolated from the Chinese tree Camptotheca acuminate, has been modified to its 9-amino, 10-hydroxycamptotecin, topotecan, and irinotecan, all of which have been found to be potent antitumor and DNA topo I inhibitory agents. Extensive structural modification of plant-derived anticancer drugs still continues because of the limited natural availability and poor water solubility of the parent compound (Dholwani et al., 2008).

Conclusion The enormous uses and possibilities of plant-derived anticancer drugs, functional foods, and nutraceuticals have been extensively described in this chapter. The way that plants and plant products defend against cancer cells and cancerous events is also included in this chapter. A number of plant products so far have been summarized for future therapeutic invention. Despite these huge plausibilities, the standardization and particularization of plant samples, their pharmacokinetic and pharmacological indices, and their molecular studies are yet to be explored comprehensively. This chapter will look for the undisclosed issues of anticancer plant products for future endeavors.

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Mi, X., Wang, C., Sun, C., Chen, X., Huo, X., Zhang, Y., Li, G., Xu, B., Zhang, J., Xie, J., Wang, Z., Li, J., 2017. Xanthohumol induces paraptosis of leukemia cells through p38 mitogen activated protein kinase signaling pathway. Oncotarget 8 (19), 31297–31304. Mizushina, Y., Shiomi, K., Kuriyama, I., Takahashi, Y., Yoshida, H., 2013. Inhibitory effects of a major soy isoflavone, genistein, on human DNA topoisomerase II activity and cancer cell proliferation. Int. J. Oncol. 43 (4), 1117–1124. Morsy, S.A., Farahat, A.A., Nasr, M.N.A., Tantawy, A.S., 2017. Synthesis, molecular modeling and anticancer activity of new coumarin containing compounds. Saudi Pharm. J. 25 (6), 873–883. Moudi, M., Go, R., Yien, C.Y.S., Nazre, M., 2013. Vinca alkaloids. Int. J. Prev. Med. 4 (11), 1231–1235. Nahum, A., Hirsch, K., Danilenko, M., Watts, C.K., Prall, O.W., Levy, J., Sharoni, Y., 2001. Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27 Kip1 in the cyclin E-cdk2 complexes. Oncogene 20 (26), 3428–3436. Panth, N., Manandhar, B., Paudel, K.R., 2017. Anticancer activity of Punica granatum (Pomegranate): A Review. Phytother. Res. 31 (4), 568–578. Paterni, I., Bertini, S., Granchi, C., Macchia, M., Minutolo, F., 2013. Estrogen receptor ligands: a patent review update. Expert Opin. Ther. Pat. 23 (10), 1247–1271. Rahmani, A.H., Alzohairy, M.A., Khan, M.A., Aly, S.M., 2014. Therapeutic implications of black seed and its constituent thymoquinone in the prevention of cancer through inactivation and activation of molecular pathways. Evid. Based Complement. Alternat. Med. 2014, 1–13. Rais, J., Jafri, A., Siddiqui, S., Tripathi, M., Arshad, M., 2016. Phytochemicals in the treatment of ovarian cancer nbsp. Front. Biosci. 9 (1), 67–75. Ranzato, E., Martinotti, S., Calabrese, C.M., Calabrese, G., 2014. Role of nutraceuticals in cancer therapy. J. Food Res. 3 (4), 18–25. Rau´l, S.C., Beatrizeatriz, H.C., Joseoziel, L.G., Francenia, S.S.N., 2017. Phenolic compounds in genus Smilax (Sarsaparilla). In: Soto-Hernandez, M., Palma-Tenango, M., del Rosario Garcia-Mateos, M. (Eds.), Phenolic Compounds—Natural Sources, Importance and Applications. InTech, Rijeka. Saed, G.M., Diamond, M.P., Fletcher, N.M., 2017. Updates of the role of oxidative stress in the pathogenesis of ovarian cancer. Gynecol. Oncol. 145 (3), 595–602. Schetter, A.J., Heegaard, N.H., Harris, C.C., 2010. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis 31 (1), 37–49. Schiller, J.H., Harrington, D., Belani, C.P., Langer, C., Sandler, A., Krook, J., Zhu, J., Johnson, D.H., Eastern Cooperative Oncology Group, 2002. Comparison of four chemotherapy regimens for advanced nonsmall-cell lung cancer. N. Engl. J. Med. 346 (2), 92–98. Schmitt, J., Ferro, A., 2013. Nutraceuticals: is there good science behind the hype? Br. J. Clin. Pharmacol. 75 (3), 585–587. Seo, H.S., Jo, J.K., Ku, J.M., Choi, H.S., Choi, Y.K., Woo, J.K., Kim, H.I., Kang, S.Y., Lee, K.M., Nam, K.W., Park, N., Jang, B.H., Shin, Y.C., Ko, S.G., 2015. Induction of caspase dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3(STAT3) signaling in HER2overexpressing BT-474breastcancercells. Biosci. Rep. 35 (6), 1–14. Shaulian, E., Karin, M., 2002. AP-1 as a regulator of cell life and death. Nat. Cell Biol. 4 (5), 131–136. Shishodia, S., Aggarwal, B.B., 2004. Guggulsterone inhibits nf-kb and ikbα kinase activation, suppresses expression of anti-apoptotic gene products and enhances apoptosis. J. Biol. Chem. 279 (45), 47148–47158. Shrivastava, S., Jeengar, M.K., Thummuri, D., Koval, A., Katanaev, V.L., Marepally, S., Naidu, V.G.M., 2017. Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β-catenin signaling cascades and reversal of epithelial–mesenchymal transition. Biofactors 43 (2), 152–169.

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Yumnam, S., Hong, G.E., Raha, S., Saralamma, V.V., Lee, H.J., Lee, W.S., Kim, E.H., Kim, G.S., 2016. Mitochondrial dysfunction and Ca2+ overload contributes to hesperidin induced paraptosis in hepatoblastoma cells, HepG2. J. Cell. Physiol. 231 (6), 1261–1268. Zeng, Y., Li, Y., Yang, J., Pu, X., Du, J., Yang, X., Yang, T., Yang, S., 2017. Therapeutic role of functional components in alliums for preventive chronic disease in human being. Evid. Based Complement. Alternat. Med. 2017, 1–13. Zhang, W., Zhang, Y., Ding, K., Zhang, H., Zhao, Q., Liu, Z., Xu, Y., 2018. Involvement of JNK1/2-NF-κBp65 in the regulation of HMGB2 in myocardial ischemia/reperfusion-induced apoptosis in human AC16 cardiomyocytes. Biomed. Pharmacother. 106, 1063–1071.

Further reading Geraets, L., Haegens, A., Brauers, K., Haydock, J.A., Vernooy, J.H., Wouters, E.F., Bast, A., Hageman, G.J., 2009. Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. Biochem. Biophys. Res. Commun. 382 (3), 598–603. Iqbal, J., Abbasi, B.A., Mahmood, T., Kanwal, S., Ali, B., Shah, S.A., Khalil, A.T., 2017. Plant-derived anticancer agents: a green anticancer approach. Asian Pac. J. Trop. Biomed. 7, 1129–1150.

14

Overview of probiotics in cancer prevention and therapy

Jiwan S. Sidhu, Dina Alkandari DEPARTMENT OF FOOD SCIENCE A ND NUTRITION, COLLEGE OF LI FE SC IENC ES, KUWAI T UN I VE RSIT Y, K UW AI T CIT Y, KU WA I T

Introduction The human body is composed of roughly 1013 cells, each of which receives several thousand DNA hits every day, mostly from reactive oxygen species (ROS) generated by the cell metabolism, Fenton reactions, and environmental toxins consumed in the diet. The cell tries to maintain a balance between the antioxidants circulating in the cells and the ROS present therein. If the ROS levels far exceed the antioxidant levels, various macromolecules such as DNA, proteins, lipids, and enzymes are damaged. The accumulated damage ultimately leads to the development of various chronic disorders, including cancer. To tackle this complex disease (various types of cancers), various approaches such as chemoprevention, irradiation treatment, and diet modification involving the increased intake of phytochemicals, probiotics, and herbal plants have emerged as the most promising and cost-effective treatments. The effect of prebiotics on the gut microflora is now being investigated, leading to the influences in the host toward many disease conditions such as gastrointestinal (GI) tract disorders, allergies, irritable bowel syndrome, and even various types of cancers (Cremon et al., 2018). Recently, the importance of GI tract microflora in improving health and the prevention of disease in humans has caught the attention of health professionals. The presence of a proper balance of prebiotics and probiotics in the human gut determines not only the beneficial influence on the host immune response, but also affects the metabolic processes and neuroendocrine pathways (Quigley, 2019). The human GI tract harbors between 100 and 1000 microbial species, which because of their symbiotic relationship play a major role in host health. Supplements consisting of probiotics, prebiotics, or synbiotics have provided promising results against various pathogenic species. Considerable research is being undertaken to study the adhesion of probiotics to epithelial tissues for pathogen exclusion and to regulate, modulate, or stimulate the host’s immune system through the activation of particular host genes (Kerry et al., 2018). Probiotics are also known to influence fat storage and regulate angiogenesis, thus providing health benefits for better living (Table 14.1). Recent advances in biotechnology are also helping us to Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00014-4 © 2020 Elsevier Inc. All rights reserved.

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Table 14.1

General contributions of probiotic organisms in human health.

Disease condition

Probiotic strains

Health benefits

Ref.

Hypercholesterolemia and CVD

Lactobacillus plantarum, Bifidobacterium bifidus, Enterococcus faecium, Propionibacterium freudenreichii Lb. casei, Lb. rhamnosus, Bf. bifidum, Bf. lactis, Streptococcus thermophilus Lb. rhamnosus, Lb. casei, Bacillus circulans, Lb. acidophilus, Bf. lactis, Lb. plantarum Lb. casei, Lb. acidophilus, Lb. rhamnosus, Bifidobacterium spp., Propionibacterium spp.

Positive (reduced dietary cholesterol absorption)

Kerry et al. (2018), Cremon et al. (2018), Chua et al. (2017), Pereira et al. (2018)

Positive (compete with pathogenic bacteria on epithelial cells) Positive (enhanced level of immune reactive cells)

Parvez et al. (2006), Cremon et al. (2018), Chua et al. (2017)

Diarrhea

Immunity

Cancer

Positive (remove ingested toxins, enhance apoptosis)

Pancreatitis

Bf. Lactis BB-12. Lb. rhamnosus GG

Food allergies

E. coli, Bifidobacterium spp., Lactobacillus spp.

Urinary tract infections and genitourinary cancers Inflammatory bowel disease

Lb. rhamnosus, Lb. reuteri, Lb. acidophilus

Positive (decreased occurrence of pancreatic infections) Improved immunity of body and reduced food allergies Urinary tract infections are reduced

Saccharomyces boulardii, Bifidobacterium spp., Lactobacillus spp.

Inflammatory bowel syndrome disease reduced

Cremon et al. (2018), Pereira et al. (2018), Gopalakrishnan et al. (2018) Chua et al. (2017), Pereira et al. (2018), Tan et al. (2019), Chang et al. (2019), Dasari et al. (2017), Gopalakrishnan et al. (2018) Tan et al. (2019), Chang et al. (2019) Chua et al. (2017)

Markowski et al. (2019)

Chua et al. (2017), Chang et al. (2019)

Adapted from Panghal, A., Janghu, S., Virkar, K., Gat, Y., Kumar, V., Chhikara, N., 2018. Potential non-dairy probiotic products—a healthy approach. Food Biosci. 21, 80–89.

identify useful health-benefitting probiotics or to genetically modify these probiotics to specifically target various diseases, including cancer, to provide improved health benefits (Chua et al., 2017; Douillard and Vos, 2019). Because of international competition and the consumer’s awareness about the health benefits of functional foods, innovators in the food industry face challenges to develop newer and more effective probiotic-rich foods. Pereira et al. (2018) reviewed the recent developments, strategies, and methods to select probiotics that offer immunostimulatory, cholesterol-lowering, antiobesity, antianxiety, antidiabetic, antiinflammatory, anticarcinogenic, and antidepressive properties. Now, the next generation of probiotics such as Christensenella minuta and Prevotella copri, to mitigate insulin resistance, Akkermansia municiphila, Bacteroides thetaiotaomicron, and Parabacteroides goldsteinii to tackle obesity and insulin resistance problems, Faecalibacterium prausnitzii that prevents intestinal

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diseases in mice, whereas anti-inflammatory and anticancer effects of Bacteroides fragilis and Bacteriodes xylanisolvens, are reported (Chang et al., 2019; Tan et al., 2019). A word of caution is that these probiotics are not universally effective and safe, and in the case of individuals with weaker immunity, they may encourage the growth of pathogens, leading to life-threatening pneumonia, endocarditis, and sepsis (Kothari et al., 2019).

General health benefits of probiotics Probiotics are friendly microorganisms living in our GI tract that offer many health benefits. Aarti et al. (2018) reported that the Lactobacillus pentosus LAP1 strain exhibited not only significant antibiofilm-forming property against Candida spp., but was also tolerant to the acidic pH of gastric juice as well as bile salts, showed hyperproteolytic activity. Recently, in a similar study, Tarrah et al. (2019) reported that L. paracasei DAT81 and L. paracasei DTA93 strains were superior in tolerance to acidic pH, bile salts, and the antibiofilm property of Escherichia coli and Listeria innocua compared to the commercially used L. rhamnosus GG strain. Now, with the development of the CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats), a system for precision genetic engineering, the production of designer Lactobacilli such as Streptococcus thermophillus has become much easier to establish their immunostimulatory functions in dairy products (Goh and Barrangoh, 2019). As per the latest survey conducted by ValdovinosGarcia et al. (2018), a large majority of gastroenterologists (97%) and nutritionists (98%) have evaluated probiotics as effective in GI tract management and declared them to be safe (Fig. 14.1). As oxidative stress has been implicated in the pathology of many diseases, the use of probiotic and synbiotic supplementation in reducing oxidative stress has been evaluated by many researchers (Zhao et al., 2017; Heshmati et al., 2018; Roshan et al., 2019). They reported that such supplements improved various biomarkers of oxidative stress such as antioxidant enzymes and glutathione levels. However, more studies are needed to discern their effect on superoxide dismutase and total antioxidant capacity. A number of antihypertensive bioactive peptides released during the hydrolysis of milk proteins by probiotics have been reported by Abtesh et al. (2018), but they suggested long-term studies to examine the importance of fermented dairy products in improving human health. In aging mice, the production of beneficial short-chain fatty acids from D-galactose by probiotics has been reported to improve memory and learning abilities (Ho et al., 2018). In lab murine models, the ingestion of probiotics to achieve a healthy gut microbiome with Lactobacillus spp. has been suggested for mitigating acute stress-induced depression (Abdrabou et al., 2018). Lately, renewed interest in studying the relationship between major depressive disorder (MDD), the gut microbiome, and the possible benefits of consuming probiotics has been reported (Park et al., 2018). In their review, they suggested the use of probiotics as a promising treatment to alleviate the inflammatory response commonly found in such patients. Kim and Shin (2019) recently reported that the intake of

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Stimulate secretion of IFN-g and IL-10

Effective immune response against pathogens

Modulate host immunity

Probiotics general benefits

Detoxify xenobiotics

Bifidobacterium and Saccharomyces boulardii

Produce microbial products and host metabolites

Regulate intestinal epithelial barrier functions

Intestinal defense against enterohaemorrhagic E. coli

Absorption of certain minerals (Ca, Fe, Mg) Ferment indigestible dietary fiber

Production of certain vitamins (K, folate, biotin, B12)

Lactobacillus species Protection against cancer and allergy development

Modulate intestinal gas production

Production of SCFA

Modulation of immune response

FIG. 14.1 General benefits of probiotics in health and disease prevention.

probiotic food may offer benefits in depression, especially in men, but suggested further studies to explore the action between probiotics and depression. Until better vaccines are developed, the use of probiotics for preventing and treating various infectious diseases has been proposed by Rotami et al. (2018). In another study, the ingestion of Bifidobacterium animalis subsp. lactis BB-12 and Lactobacillus rhamnosus GG increased the matrix metalloproteinases (MMP)-9 but decreased the tissue inhibitor of metalloproteinases (TIMP)-1, indicating that probiotics have immunomodulatory effects in the oral cavity (Jasberg et al., 2018).

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Probiotics in immune modulation During the last few years, significant progress has been made in the area of preventive medicine, especially related to the role of functional foods, probiotics, and prebiotics in health promotion and disease prevention through boosting multiple physiological functions such as immune modulation (Yahfouli et al., 2018). A multistrain probiotic preparation consisting of L. rhamnosus, B. lactis, and B. longum has been reported to significantly increase (70%) antiinflammatory cytokine interleukin (IL-10) production and decrease (80%) the secretion of proinflammatory cytokines IL-1β and IL-6 (Sichetti et al., 2018). Marinelli et al. (2017) reviewed advances in the mechanism of how probiotics and the body’s immune system work together to boost the effectiveness of antitumor drugs in cancer control. In a meta-analysis, Maia et al. (2019) reported that probiotic therapy can potentially modulate the inflammatory process by increasing antiinflammatory markers and by decreasing the proinflammatory markers such as tumor necrosis factor-α and the C-reactive protein. In another study, Devi et al. (2018) also showed that Lactobacillus spp. (especially L. paraplantarum) isolated from fermented foods downregulated the gene expression of proinflammatory cytokines such as TNF-α, IL-1α, IL-1β, IL-6, and IL-8, but upregulated the antiinflammatory cytokines such as TGFβ1, IL-4, and IL-10. Recently, a probiotic formulation containing the L. bulgaricus DWT1 strain has been reported to inhibit tumor growth by activating proinflammatory responses in macrophages (Guha et al., 2019). Now, probiotics are well known to exert beneficial effects in inflammatory bowel disease through changes in the miRNAs as well as through the gut microbiome composition. Rodriguez-Nogales et al. (2018) investigated the antiinflammatory effect of probiotic Saccharomyces boulardii in dextran sodium sulfate (DSS)-induced colitis. According to them, the probiotic reduced the colonic damage caused by DSS by reducing the disease activity index by increasing bacterial diversity and alterations in miRNA expression. In the case of autism spectrum disorder (ASD), the immune system is one of the routes for gut-to-brain communication. But Doenyas (2018) has suggested the possible mechanisms of gut microflora and the neural basis of ASD inflammation, and they have suggested to mothers at risk of giving birth to children with ASD to follow intervention by using probiotics. A study by Noci et al. (2018) stated that using aerosolized L. rhamnosus strongly promoted immunity against B16 lung metastases and enhanced responses to chemotherapy.

Probiotics, Helicobacter pylori, and stomach cancer Probiotics have been reported to promote human health. Bifidobacterium longum subsp. longum BB536 has the capacity to modulate gut microbiota to influence the gut metabolism, stabilize the gut microbiota, and achieve good homeostatic balance within the host-microbiome interactions (Wong et al., 2019). A few studies on the therapy of H. pylori to prove the usefulness of probiotics (Eslami et al., 2019), review and meta-analysis of

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eradication therapy (Wang et al., 2017a), L. fermentum UCO-979C having a significant anti-H. pylori activity (Garcia et al., 2017), throat and gut microbiota supplementation with probiotics in humans (Wang et al., 2017b) and on gut microenvironment homeostasis (Chen et al., 2018), elevated anti-H. pylori effect of L. fermentum UCO-979C probiotic strain encapsulated with carrageenan under fasting conditions (Gtuierrez-Zamorano et al., 2018), have been reported. The potential role of probiotics in enhancing the quality of life of individuals suffering from ulcerative colitis (Van der Waal et al., 2019) and gut dysbiosis and irritable bowel syndrome (Principi et al., 2018) have recently been investigated. The consumption of probiotics to improve the lipid profile, glycemic control, oxidative stress and inflammation, with the production of short-chain fatty acids (SCFA) in type-2-diabetes (T2D) (Tonucci et al., 2017; Razmpoosh et al., 2019), beneficial metabolic effects in diabetic hemodialysis patients (Soleimani et al., 2017), effect of yogurt containing probiotics on endothelial dysfunction markers and the glycemic indexes in patients with metabolic syndrome (Rezazadeh et al., 2019), and improved gut microbiota dysbiosis in obese mice fed a high-sucrose or high fat diet (Kong et al., 2019), have been reported. As a therapeutic target, the gut microbiota has a significant role in the host metabolism, and its dysregulation is reported to result in cardiometabolic disorders such as T2D, arterial hypertension, chronic kidney disease (CKD) and dyslipidemia (Neto et al., 2018), enhanced iron absorption in pediatric patients with iron deficiency (Rosen et al., 2019), as an adjuvant therapy for prevention and management of depression (Gayathri and Rashmi, 2017), laxative effect on loperamide-induced constipation in rats (Eor et al., 2019), to attenuate the progression of Alzheimer’s disease in transgenic mice (Abraham et al., 2019). The benefits of probiotic consumption are not only the detoxification of microbial toxins and xenobiotics, the modification of bile salts, the biosynthesis of vitamin K, folic acid, vitamin B12, absorption of iron, magnesium and calcium, and lactose fermentation, but is also reported to provide immunomodulatory effects to treat autoimmune diseases and allergies (Saladino et al., 2018; Dargahi et al., 2019; Yousefi et al., 2019).

General influence of gut microbiome on cancer Cancer is known to be a very complicated disease, as are its prevention and cure. Each type of cancer has unique targets such as immune regulatory mechanisms and signals, apoptotic signals, and proteins and enzymes involved in its development and cure. The microbiota constantly change, but due to ongoing and dynamic interaction among different parts of the immune system, a homeostasis is maintained. If this balance is disrupted, such as due to dysbiosis, it can lead to many chronic pathological conditions, including cancer (Cogdill et al., 2018). Now, fecal microbiota transplantation (FMT) and probiotics administration have become two important approaches to change the gut microbiome, especially for infections occurring after colorectal surgeries, Clostridium difficile colitis, and inflammatory bowel disease (Yeh and Morowitz, 2018). The metabolites of a yeast, Kluyveromyces marxianus AS41, have been reported to induce apoptosis in different

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human cancer cell lines, but show no effect on normal cells while also exhibiting an antipathogenic effect (Saber et al., 2017a, b). Because the gut microbiome affects the response to various cancer therapy approaches, the information about the microbiome for its effects on the immune response and cancer is receiving more attention. Moreover, it is pertinent to examine the factors affecting the gut microbiota and various approaches to manipulating these microorganisms to elicit improved therapeutic responses (Gopalakrishnan et al., 2018). The gut microbiome has recently become very crucial, as these microorganisms are known to mediate a fine balance between diseases and human health (Li et al., 2019). According to them, the gut microbiome influences the efficiency of cancer immunotherapy (Fig. 14.2). Probiotic bacteria were investigated for their role as therapeutic agents in the prevention and cure of various types of cancers (Chen et al., 2019; McQuade et al., 2019; Goubet et al., 2018). Dasari et al. (2017) have reviewed the molecular and cellular mechanisms of probiotics in cancer prophylaxis and the therapy of various cancers as well as the safety concerns of probiotics when used in nutritional and therapeutic diet management.

Possible challenges

1.

2.

3.

Harmful bacteria in the GI tract

Making use of best FMT donor

Other important options: Such as, diet, physical exercise, sleep cycles, medications

Strategies for improvement Lower the efficacy of immunotherapy

Solutions: 1. Use antibiotics to eliminate these harmful bacteria 2. Use Prebiotics 3. Use Synbiotics

Approaches: 1.Screening & selection of favorable bacteria (Bifidobacteria spp.) 2. Elimination of pathogens from this selection 3. Narrow down the choice to the most beneficial bacteria

Individuals adjust themselves to these factors to enhance antitumor immunity

FIG. 14.2 Causes and strategies for controlling cancer through probiotics.

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Probiotics in colorectal cancer The composition of the gut microbiota is considered to be an important risk factor for the initiation and progression of colorectal cancer, but probiotics are reported to positively modulate the composition of this gut microbiota (Meng et al., 2018). In a review, dos Reis et al. (2017) outlined the mechanism of probiotic actions, such as their influence on the type of gut microbiota resulting in metabolic activity and host physiology; the binding and degradation of carcinogens present in the intestines; the improvement of epithelial barriers; immunomodulation; the production of anticarcinogenic compounds in the gut; cell proliferation inhibition; and the apoptosis of cancer cells. Additionally, some reports have also pointed out the adverse effects of oral supplementation of probiotics. They pointed out the importance of more studies regarding the identification of probiotic strains with improved anticarcinogenic potential, viability in the GI tract, dosage levels, and frequency of intake of these probiotics. Ankaiah et al. (2017) isolated and then cloned a probiotic, Enterococcus faecium por1, that expressed a bacteriocin, enterocin-A, that showed anticancer effects against gastric, human colon, and cervical cancer cell lines; at the same time, however, it had no cytotoxicity toward normal epithelial cells in the intestines. Saber et al. (2017a, b) identified a probiotic yeast, Pichia kudriavzevii AS-12, that secretes metabolites having anticancer effects against colon cancer cells by inhibiting growth and inducing apoptosis, but showing no cytotoxicity toward normal cells. While examining the total genomics of Bifidobacterium animalis subsp. lactis BL3, Kang et al. (2017) showed it to prevent acute colitis and colon cancer. Leuconostoc mesenteroides has been shown to reduce inflammation and induce apoptosis in colon cancer cells by modulating the NF-кB/AKT/PTEN/MAPK pathways, thus serving as an alternate or complimentary cancer therapy (Vahed et al., 2017). The leading causes of colorectal cancer are now being identified as mainly lifestyle factors, but genetics are not much impressible. A lack of physical exercise, an altered diet, and increased alcohol intake have led to dysbiosis of GI tract microbiota, resulting in a higher burden of colorectal cancer. The use of prebiotics and probiotics has been suggested to maintain gut microbial homeostasis, which can alleviate these pathological and dysbiosis processes by encouraging antiinflammatory and anticarcinogenic properties, an epithelial barrier, carcinogen inactivation, and proapoptosis mechanisms (Rossi et al., 2018; Weng et al., 2019). Nisin A, a lantibiotic bacteriocin and antibacterial peptide, is being used as a food preservative, mostly for milk-based products such as processed cheeses. Norouzi et al. (2018) reported that nisin suppressed the metastasis process in colorectal cancer cell lines by downregulating MMP2F, MMP9F, CEA, CEAM6, and metastatic genes. Some of the food additives such as propyl gallate and tert-butylhydroquinone have been shown to influence probiotic metabolomics, which could subsequently alter the progression of colorectal cancer in humans (Salmanzadeh et al., 2018). Recently, probiotic Lactobacillus rhamnosus and a regular consumption of kefir have been reported to modulate the composition of gut microbiota, leading to the attenuation of preneoplastic colorectal Aberrant crypt foci while offering protective effects against mycotoxin (zearalenone) toxicity mediated by oxidative stress in cultured HCT-116 colorectal cells (Gamallat et al., 2019; dos Reis et al., 2019; Golli-Bennour et al., 2019).

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Probiotics and upper body cancers Generally, the squamous cell carcinomas that originate from the lips, oral cavity, larynx, paranasal sinuses, and pharynx regions are responsible for the development of head and neck cancers. These cancers are generally treated with chemotherapy, radiotherapy, and surgery. Because of the damage done to intestinal epithelial barriers during chemotherapy, intestinal bacteria are translocated to the bloodstream, where they are then translocated to cause sepsis in the neck and head. Proper and continuous use of probiotics has been shown to prevent the translocation and proliferation of pathogenic bacteria causing sepsis in these organs (Gunduz et al., 2018). The use of probiotics has also been reported to improve the survival rate of patients suffering from lung cancer due to immunomodulation and augmented expression of tumor suppression genes (Sharma et al., 2018). Milk fermented by Lactobacillus casei CRL431 has been shown to fight tumor cell metastasis from the breast to the lungs via modulation of immune cells in a murine model (Utz et al., 2019). The extracellular vesicles derived from a probiotic, Lactobacillus rhamnosus GG, have been reported to exhibit a significant cytotoxic effect on the hepatic cancer cell lines, causing cancer cell death (Behzadi et al., 2017). Probiotics such as Lactobacillus acidophilus and Bifidobactrum bifdioum are reported to control hepatic cancer progression by delaying the metastasis process and reducing inflammation (Heydari et al., 2019). They proposed the mechanism as downregulation of oncogenes/oncomirs or upregulation of tumor suppression genes/microRNAs. The direct and indirect effects of probiotics on lung cancer are summarized in Fig. 14.3. One of the most common endocrine disorders among women today is polycystic ovary syndrome (PCOS), resulting from elevated inflammation. The feeding of four strains of a probiotic organism, Lactobacillus, enhanced the level of antiinflammatory interleukin (IL10) when compared with a placebo; it also decreased the proinflammatory IL-6 and hs-CRP but did not affect the TNF-α levels (Ghanei et al., 2018). A review by Anderson et al. (2017) on the effect of probiotics on gastrointestinal, respiratory, and nutritional outcomes in people with cystic fibrosis has brought out the importance that using probiotics improves respiratory and gastrointestinal functions with no adverse effects. Radiotherapy-induced diarrhea (RID) is very common among patients suffering from abdominal and pelvic cancers. The use of probiotics is beneficial in preventing chemotherapy- or radiotherapy-induced diarrhea, as probiotics rarely produce any severe harmful effects during cervical cancer treatment (Aviles-Jimenez et al., 2017; Qiu et al., 2019). In a recent publication, Sethi et al. (2019) extensively reviewed the important role of microorganisms in immune system growth and development, microbe-induced immune system activation promoting oncogenesis, especially on the pancreatic carcinogenesis, and how the attenuation of microbiome improves the anticancer immune response, thus enabling the beneficial immunotherapy approach against this disease. In a recent collaborative review, Markowski et al. (2019) presented evidence that microflora residing in the genitourinary tract may affect the development of malignancies related to kidney, bladder, and prostate cancers as well as their treatments using probiotics.

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Lactobacillus acidophilus

Bifidobacterium infantis

Direct effects

Development of lung cancer

Prevention

Indirect effects

Effects of heavy metals and γ-benzpyrene FIG. 14.3 Role of probiotics in lung cancer.

Delivery systems for probiotics There are a number of potential health benefits from consuming probiotics, as these microorganisms produce specific bioactive metabolites (probioactives) that contribute to health functionality (Champagne et al., 2018). Obviously, to achieve significant health benefits, the challenge is that these probiotics must be delivered to the GI tract in sufficient viable numbers to produce effector probioactive molecules such as acetic, propionic, and butyric acids (SCFA). The clinical effects of these probiotics are affected by genetic expression as well as technological production factors. Consequently, a number of product formulations and microencapsulation techniques are being investigated to achieve enhanced health benefits from foods containing probiotics, as reviewed in the following section:

Dairy-based probiotic foods The health-promoting properties of probiotics are now well established. Zoumpopoulou et al. (2017) reviewed the role of probiotics, including genetically modified strains, in promoting gut and immune health as well as their role in oral health, cancer, obesity, and related diseases. The probiotic potential of a Lactobacillus rhamnosus strain isolated from ripened cheese has been investigated by Bautista-Gallego et al. (2019); the strain reduced

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the relative number of Bacteroides but increased the number of Prevotella in the feces. A number of studies on fermented milk-based products such as yogurt have shown improved slow-transit constipation (Liu et al., 2017). Yogurt containing rice bran improved probiotic viability and offered higher antioxidant benefits (Demirci et al., 2017). The milk fat level showed no adverse effects on the Lactobacillus acidophilus in yogurt (Tavakoli et al., 2019). Streptococcus thermophilus in yogurt is a promising probiotic (Uriot et al., 2017). The formulation of functional yogurt containing probiotics, prebiotics, synbiotics, and bioactive phytochemicals (Fazilah et al., 2018), goat milk containing probiotics such as Lactobacillus alimentarius DDL48, Lactobacillus reuteri DDL19, Enterococcus faecium DDE39, and Bifidobacterium bifidum DDBA, offering health benefits (Utz et al., 2018), camel milk fermented with Lactococcus lactis KXSS1782 showing anticancer, antihypertensive, antidiabetic, and antioxidant activities (Ayyash et al., 2017), nutraceutical properties of Himalayan cheese (Kalari) fermented with L. plantarum NCDC012, Lactobacillus casei NCDC297 (Mushtaq et al., 2019), preparation of functionalized whey powder containing Propionibacterium freudenreichii, are some of the technological developments to deliver probiotics for achieving significant health benefits.

Meat-based probiotic foods In the preparation of traditional fermented foods in any region of the world, a variety of substrates are used and usually lactic acid bacteria (LABs) are the starter cultures. For centuries, Utonga-kupsu has been a traditional fermented fish product prepared by using LABs in Manipur in Northeastern India. Singh et al. (2018a, b) reported that this product exhibits potent probiotic and anticancer properties. Ayyash et al. (2018) prepared semidry fermented camel sausages with the Lactobacillus plantarum KX881772 strain isolated from camel milk. This novel functional food (the fermented camel sausage) showed significantly higher angiotensin converting enzyme (ACE) inhibition and cytotoxicity against the Caco-2 cell line than regular fermented beef sausage. Using three types of dietary fiber sources (arabinogalactan, citrus fiber, and inulin), an herbal extract, and a probiotic, Lactobacillus rhamnosus, Perez-Burillo et al. (2019) prepared a dry fermented salami with improved antioxidant capacity and beneficial health markers with this functional product.

Plant-based probiotic yogurt Among the functional food segments, probiotic, prebiotic, and symbiotic dairy foods hold an important place. Moreover, the organic vegetarian food market is also growing rapidly, mainly because of the consumer demand for such food products. Batista et al. (2017) prepared a symbiotic fermented milk product using probiotic bacteria and up to 3% organic green banana flour. This product showed lower thrombogenic and atherogenic indices with a better flavor profile than a lower amount of green banana flour (1%) and had a shelf life of 21 days. Probiotic bacteria are being added to many dairy functional food products to provide health benefits. De Azevedo et al. (2018) prepared fermented skim milk supplemented with grape pomace extract (rich in polyphenolics) using Lactobacillus

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acidophilus and Streptococcus thermophilus. These two probiotics were shown to only metabolize the polyphenolics to some extent and had improved cell viability, thus providing a potential fermented food with functional health properties. Soy yogurt prepared with mulberry leaf extract and Lactobacillus casei 01 and Lactobacillus acidophilus LAS had a shelf life of 30 days at 4oC and had a higher antioxidant capacity with good consumer acceptability and minimal cell loss during the refrigerated storage period (Kemsawasd and Chaikham, 2018). Recently, Mousavi et al. (2019) prepared a flaxseed-enriched stirred probiotic yogurt using Lactobacillus acidophilus, and the finished product showed improved physicochemical, textural, and sensory qualities up to a refrigerated storage period of 13 days when the flaxseed addition was limited to 4% or less. A Lactobacillus acidophilus-containing probiotic beverage based on whey, pearl millet, and barley has been reported to inhibit the Shigella pathogen in a mouse model (Ganguly et al., 2019). When immobilized on soybeans, Lactobacillus casei CSL3 isolated from colostrum was shown to possess probiotic potential in vitro; it was also microbiologically safe and had good cell viability (Vitola et al., 2018). Moumita et al. (2018) developed a functional food based on soya milk, bovine milk, and green tea extract with the probiotic Enterococcus faecium that had very good cell viability.

Encapsulation of probiotics for better delivery As probiotics are live organisms, they must stay viable until they reach the colon in sufficiently large numbers to offer health benefits to consumers. The most important objective of all probiotic food companies is to obtain the highest viability in their probiotic cultures. To achieve this objective, a number of techniques such as freeze drying, foam drying, spray drying, cryogenic preservation, and encapsulation have been investigated. Libran et al. (2017) investigated a new electrospray-coating atomization method to preserve the viability of probiotics. When used for encapsulating probiotics using whey protein concentrate, this technology gave a significantly longer viability of the probiotics that reached 1 year at room temperature when compared with freeze drying. Lactobacillus acidophilus and Bifidobacterium bifidum coated with calcium alginate and cell wall materials of Saccharomyces cerevisiae showed enhanced resistance to simulated gastric juices (Mokhtari et al., 2017). The encapsulation of probiotic Lactobacillus plantarum with alginate-arabinoxylan (Wu and Zhang, 2018), Lactobacillus rhamnosus GG with carboxymethyl cellulose and chitosan (Singh et al., 2018a, b), and Pediococcus acidilactici isolated from raw camel milk with camel whey protein microparticulates (Ahmad et al., 2019) has been shown to obtain enhanced cell viability during storage. Lactobacillus plantarum CECT220 and L. casei CECT475 probiotics encapsulated with soybean protein concentrate prepared by Gonzalez-Ferero et al. (2018) showed enhanced cell viability against simulated gastrointestinal fluids as compared with the commercial forms available. Calabuig-Jimenez et al. (2019) microencapsulated Lactobacillus salivarius spp. salivarius in mandarin juice using high-pressure homogenization and reported it to be stable under adverse GIT conditions. Seven strains of yeast isolated from virgin olive oil, (e.g., Candida

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diddensiae, Candida adriatica, Nakazawaea wickerhamii, Wickerhamomyces anomalus, Nakazawaea molendini-olei, and Yamadazymatervintena) were compared for their survival under gastric conditions with Saccharomyces boulardii as a reference by Zullo and Ciafardini (2019). Encapsulation of these probiotic strains with olive oil improved their survival in GIT. W. anomalus appeared to be the best probiotic among these strains. Lozenges produced from a probiotic Enterococcus faecium CRL183 using inulin survived in saliva and inhibited the growth of the Streptococcus mutans ATCC 25175 strain that is known to cause dental caries (Witzler et al., 2017).

Plant-based, nondairy probiotic foods Today’s consumers are well informed about the importance of healthy eating for attaining health benefits more than the general nutrition. Probiotics are viable microorganisms eaten by consumers through a wide variety of foods, mostly dairy-based products. Because of the cholesterol considerations, research now is being diverted toward nondairy based foods such as legumes, cereals, fruits, and vegetables (Panghal et al., 2018). The formulation and development of various probiotic foods based on nondairy sources will be reviewed in the following section. As many fruits are rich in phenolic compounds, it becomes imperative to study the effect of these phytochemicals on the viability of probiotics in such food matrices. Sireswar et al. (2017) investigated the effect of sea buckthorn juice and an apple juice matrix supplemented with a few probiotics such as L. rhamnosus GG, L. plantarum, L. casei, and L. acidophilus on the eradication of enteropathogenic E. coli, Shigella dysenteriae, Salmonella enteritidis, and Shigella flexneri. They found sea buckthorn juice to be a superior matrix to suppress the growth of these pathogens. Emser et al. (2017) prepared a probiotic cut apple with L. plantarum by osmotic dehydration. The product maintained the viability of the probiotic organism for 6 days in storage at chilling temperatures and also survived gastrointestinal conditions. Akman et al. (2019) developed a snack based on dried apple slices impregnated with probiotic L. paracasei, and the vacuum-dried product had acceptable sensory quality and bioactive properties. The health-promoting benefits of grains can be improved by probiotic fermentation, depending upon the type of grain as well as the probiotic species. Ayyash et al. (2018) employed a solid-state fermentation process using quinoa, lupin, and wheat by three probiotics: Bifidobacterium animalis, B. breve, and B. longum. They found that the fermented lupin product showed five-fold and three-fold cytotoxicity against colon cancer cells (Caco-2) and breast cancer cells (MCF-7), respectively. The probiotic Lactobacillus brevis isolated from rice bran sourdough has been shown to exhibit antifungal effects on the tested fungi, antibacterial activity against Listeria monocytogenes, and antiaflatoxigenic effect against aflatoxin B1 in a mouse model (Sadeghi et al., 2019). A number of studies have recently been reported about the effect on human health of probiotics present in fermented fruit and vegetable products. A number of probiotics isolated from a Korean product, jangajji (prepared from garlic, pepper leaves, cucumber,

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radish, and a few other vegetables), by Son et al. (2018) were identified as Leuconostoc citreum, Lactobacillus paraplantarum, and Pediococcus pentosaceus. Among these probiotics, Lactobacillus paraplantarum exhibited higher nitric oxide production, antioxidant activity, and immunostimulatory activity while its mRNA expression level for iNOS, IL-1β, TNF-α, and IL-6 were found to be better than L. rhamnosus GG. Fruit juice is one of the most widely consumed beverages worldwide. Fruit juices are known to be rich not only in many vitamins, minerals, and health-promoting phytochemicals, but are also devoid of fat and cholesterol. Oh et al. (2017) developed fermented blueberry juice with a few probiotics isolated from fermented starfish such as Lactobacillus brevi and Bacillus amyloliquefaciens and a yeast, Starmerella bombicola. The fermented blueberry product not only showed significant antioxidant capacity but also had a good shelf life when compared with the poor shelf life of fresh blueberries. Being rich in dietary fiber and polyphenolic antioxidants, the byproducts of passion fruit, guava, and orange have been added to cereal-based and goat milk-fermented products by Casarotti et al. (2018). These fruit byproduct-based fermented foods were shown to enhance the viability of probiotics in gastrointestinal tract conditions. The pectin extracted from the passion fruit peel has been utilized in producing both a fermented as well as a nonfermented beverage using the L. rhamnosus ATCC7469 strain; the probiotic present in this product showed very good stability to gastrointestinal conditions (Santos et al., 2017). Selenium (Se) is an essential trace mineral known to perform a synergistic role for vitamin E in human health and is a part of several enzymes. Xu et al. (2019) prepared a blended juice consisting of apple, carrot, orange, and Chinese jujube, and fermented it using 1% Se-enriched Streptococcus thermophilus starter; this fermented blend was found to be rich in many flavor compounds. Majeed et al. (2018) investigated the stability of probiotic Bacillus coagulans MTCC5856 in brewed tea and coffee beverages that exhibited synergistic properties when a soluble dietary fiber source was also added. These probiotic tea and coffee beverages had a shelf life of 2 years at room temperature. The probiotic B. coagulans showed a very high survival capacity in coffee (94.94%) and tea (99.76%) and grew well in the hostile conditions in the GIT. Two probiotics, Bacillus subtilis, subsp. Inquasporium KR816099, and Lactobacillus fermentum KT183369, isolated from coconut toddy were shown to exhibit good adhesive properties, both in vivo and in vitro, using aquatic fish as well as its pathogen, Vibrio parahaemolyticus (Krishnamoorthy et al., 2018). In another study, a new functional beverage prepared from coconut water obtained from fully mature has been prepared using a potential probiotic, Lactobacillus plantarum DW12, by Kantachote et al. (2017). As per their study, this beverage was found to be rich in vitamin B12 and exhibited significant antioxidant activities, thus promoting human health.

Conclusion From the above review, it seems clear that probiotics in foods play an important role in reducing the incidences of many metabolic and physiological diseases in humans. Probiotics have been investigated for their role in reducing infections in the gastrointestinal tract

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and urinary tract. They have also been investigated for helping reduce the incidences of obesity, diabetes, hypertension, and cardiovascular diseases while strengthening the immune system and reducing various types of cancers. The biggest challenges health professionals still face are an efficient delivery system of viable probiotics to the small intestine without them getting killed by the harsh stomach acidity conditions, in adequate numbers, enough stability, survival, and persistence in the large intestine. More research is needed to genetically modify these probiotics to increase their stability and effectiveness under the harsh conditions of the GI tract. The role of various prebiotics to improve the effectiveness of probiotics also needs more serious attention.

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Further reading Ayyash, M., Liu, S.Q., Al-Mheiri, A., Al-Dhaheri, M., Raeisi, B., Al-Nabulsi, A., Osaili, T., Olaimat, A., 2019. In vitro investigation of health-promoting benefits of fermented camel milk sausage by novel probiotic Lactobacillus plantarum: a comparative study with beef sausages. LWT-Food Sci. Technol. 99, 346–354. Huang, S., Rabah, H., Ferret-Bernard, S., et al., 2019. Propionic fermentation by the probiotic Propionibacterium freudenreichii to functionalize whey. J. Funct. Foods 52, 620–628.

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Plant-derived functional foods with chemopreventive and therapeutic potential against breast cancer: A review of the preclinical and clinical data Peter Kubatkaa, Alena Liskovab, Martin Kelloc, Jan Mojzisc, Peter Solard, Zuzana Solarovac, Pavol Zuborb, Anthony Zullie, Jan Dankob, Yearul Kabirf a DEPARTMENT OF MEDICAL BIOLOGY , JESSENIUS FACULTY OF MEDICINE, COMENIUS UNIVERSI TY IN B RATI SLAVA, MAR TI N, SLOVAK REPUBLI C b C L I NI C O F G Y N E C OL OG Y AND OBSTETRI CS, JES SENIUS FACULTY OF MEDIC INE, CO M EN IU S UNI VE RS IT Y IN BRAT IS L A V A , MARTIN, SL OVAK REPUBLIC c DE PARTMENT OF PHAR MACOLOGY, FACULTY OF MEDICINE, UNIVERSITY OF P AVOL JOZEF Sˇ AFA´ RI K, KO Sˇ IC E, SLOVAK REPUB LIC d DEPARTMENT OF ´ R IK , K OSˇ I CE , MEDICAL BIOLOGY, FACULTY OF MEDICINE, UNIVERSITY O F PAV OL JOZ EF Sˇ AF A SLOVAK REPUB LIC e INSTITUT E F OR HE ALTH AND SPORT ( IHES) , VI CT ORI A U NI VE RSI TY , MELBOURNE, VIC, AUSTRALIA f DEPARTMENT OF BIOCHEMISTRY AND MOL ECUL AR B I OL OGY , UNIVERSITY OF DHAKA, DHAKA, BANGLADESH

Introduction In spite of great progress in research, diagnosis, and therapy, cancer is still a serious health problem and, with cardiovascular diseases, is a leading cause of death worldwide. With the exception of nonmelanoma skin tumors, breast cancer (BC) is the second most frequent malignancy and has remained one of the most common neoplasia among women in the world (Golubnitschaja et al., 2016). Around 2 million new BC patients and 500,000 BC deaths are recorded per year, meaning that this disease has reached an epidemic scale in the early 21st century (Golubnitschaja et al., 2016). In this regard, cancer chemoprevention is a potentially effective tool for BC risk reduction, targeting both the genetic components of breast carcinogenesis and the epigenetic changes that are consequential for the initiation and development of sporadic BC consisting over 90% of all cases (Golubnitschaja, 2017). Moreover, cancer chemoprevention is well tolerated and is supposed to be effective, less toxic, and more economically profitable in comparison with BC therapy. Functional Foods in Cancer Prevention and Therapy. https://doi.org/10.1016/B978-0-12-816151-7.00015-6 © 2020 Elsevier Inc. All rights reserved.

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A decrease in the occurrence of cancer and other diseases of civilization is associated with the regular consumption of phytochemicals present in whole plant (functional) foods (Liu, 2013a, 2013b). The evidence from epidemiological, preclinical, and clinical trials indicates that diets rich in plants, meaning they include phenolic compounds, terpenoids, or other phytochemicals, display anticancer or other biological effects, including neuroprotective, antiallergic, antiinflammatory, or antiaggregagoty effects (Yiannakopoulou, 2014). The mechanisms of action of phytochemicals may involve an ability to target multiple molecular pathways in carcinogenesis (e.g., proliferation, apoptosis, angiogenesis, inflammation, cell infiltration, cancer stem cells, or epigenome) with no undesirable side effects in cells. Extensive research strongly suggests that the synergistic or additive efficiency of phytochemicals present in whole plant-derived foods may be associated with their effective pleiotropic activities in the cell and consequently the anticancer effects (Kapinova et al., 2017). On the other hand, it is supposed that the single plant-derived molecule could either lose its biological activity or may not affect the same pathways as the molecules in whole plant-derived functional foods (i.e., its tumor-suppressive activity may be much weaker) (Liu, 2013a; Kapinova et al., 2018). Traditional medicine (e.g., Chinese, Ayurvedic) belongs among alternative medical care systems that have originated over thousands of years; it has been intensively applied in controlling cancer growth. Natural plant molecules, herbs, and spices and combination formulas used in traditional medicine could provide therapeutic effects against tumor cells and chemoprevention activity by suppressing the initiation and development of carcinogenesis without serious undesirable side effects. For these reasons, the traditional medicinal approach has become an important sector within oncology practice (Wang et al., 2014; Kulkarni et al., 2014). Using traditional medicine, the tumor-suppressive effects of combining numerous plant substances containing various phytochemicals that target a plethora of cell signaling pathways should be very effective for specific indications such as cancer risk reduction in high-risk individuals or a maintenance therapeutic approach. This chapter provides up-to-date knowledge about the anticancer properties of phytochemicals present in whole foods related to affecting signaling pathways involved in mammary carcinogenesis. The potential clinical utility of the natural mixtures of phytochemicals present in plant-derived functional foods is discussed regarding prevention and therapeutic approaches within BC management.

Antioxidant and genoprotective effects of phytochemicals Numerous preclinical studies have demonstrated the antioxidative and genoprotective effects of phytochemicals in the cell. These effects include the scavenging effect, increased DNA repair activity, the expression of endogenous antioxidant enzymes, and the suppression of prooxidant enzymes. The most abundant compounds with antioxidant activities in human diets are natural polyphenols. Their radical scavenging effects are based on the substitution of hydroxyl groups in the aromatic rings of

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phenolics (Rokayya et al., 2013). In this regard, total phenolic content is in apparent correlation with the total antioxidant activity of specific phytochemical extracts of certain plant foods. The power of the antioxidant activity positively correlates with the total phenolic content (Sun et al., 2002). Indeed, the scavenging activity of grape seed extract against the ABTS radical was strongly associated with the level of phenolic compounds (Sung and Lee, 2010). Ramos et al. (2008, 2010) demonstrated that the polyphenols luteolin and luteolin-7-glucoside as well as the water extracts of the Salvia species increased the rejoining of H2O2-induced strand breaks in Caco-2 cells. Moreover, carotenoids such as β-cryptoxanthin increased the rejoining of H2O2-induced strand breaks and increased the repair of oxidized bases in HeLa and Caco-2 cells. Indeed, both in vitro (Astley et al., 2004) as well as human biomonitoring studies reported that β-carotene, lutein, and lycopene (Fillion et al., 1998; Torbergsen and Collins, 2000) as well as the consumption of kiwi and other antioxidant-rich plant products showed reduced DNA strand breaks in lymphocytes (Freese, 2006; Brevik et al., 2011). Furthermore, three weeks of a cooked carrot diet increased the repair activity and strand break rejoining in lymphocytes in vitro (Astley et al., 2004). Interestingly, the intake of antioxidant-rich plant products increased the activity of the DNA base excision repair system, but on the other hand, without explanation, reduced the activity of DNA nucleotide excision repair systems (Ramos et al., 2011). Many studies showed that phytochemicals derived from various fruits, vegetables, herbal medicines, and spices can stimulate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2,) known as a regulator of the antioxidant response and inducer of the expression of antioxidant or phase II detoxifying enzymes (Na and Surh, 2008; Sahin et al., 2010; Saw et al., 2012). In this regard, epigallocatechin-3-gallate (EGCG) induced, through the activation of the Nrf2 signaling pathway, different antioxidant enzymes such as glutathione peroxidase, catalase, and quinone reductase in the small bowels, livers, and lungs of SKH-1 hairless mice (Khan et al., 1992), but also manganese superoxide dismutase (Na et al., 2008), ɣ-glutamyltransferase 1, and heme oxygenase-1 (Zheng et al., 2012). In addition, EGCG blocked the accumulation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential induced by H2O2 via the modulation of caspases, the Bcl-2 family, and MAPK and Akt signalization in human lens epithelial cells (Yao et al., 2008). Moreover, EGCG prevented oxidative stress through the direct alteration of subcellular ROS formation, glutathione metabolism, and cytochrome P450 2E1 activity (Raza and John, 2005). In addition, phytochemicals demonstrated antioxidant effects also via the reduction of prooxidant enzyme expression (Lee et al., 2006; Li et al., 2013).

Possible targets of phytochemicals in breast cancer cell signaling Phytochemicals can modulate carcinogenic signaling pathways through several crucial mechanisms of action. Precise knowledge of the activities of phytochemicals in the cell can improve dietary choices in new chemopreventive strategies against cancer. The most important cellular targets of phytochemicals are described below (Fig. 15.1).

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FIG. 15.1 Crucial mechanisms of anticancer action of phytochemicals/plant functional foods in the cell.

Cell cycle Changes in cell cycle progression represent an early response of different cancer cell lines to several natural phytochemicals. Together with cell signaling cascade alteration, phytochemicals modulate cancer cell proliferation, apoptosis, and survival (Geng et al., 2017; Li et al., 2015). The cell cycle can be affected in any phase by the modulation of cyclindependent kinases (CDKs), the actions of which are modulated by interactions with their regulatory subunits (cyclins) and cyclin-dependent kinase inhibitors (CDKIs) (Singh et al., 2017). Cyclin D1 and cyclin E expression downregulation, CDK4/6 and CDK2 level depression, and activity inhibition mediated by several phytochemicals such as flavonoids or curcumin arrested cancer cells in the G1 phase (Zhang et al., 2018; Agarwal et al., 2018). The CDK activity, which is important for driving cells from the G1 to the S phase, is inhibited by phytochemicals that increase the expression of CDKI and its binding with CDK (Sabarwal et al., 2017). Several phytochemicals showed a strong inhibitory effect and cell cycle arrest in the G2-M phase (Zhang et al., 2016; Cheng et al., 2016). The activity of Cdc2 kinase demonstrates a fundamental role during cellular alterations linked with the G2-M transitions, and is significantly affected by the modulations of cyclin B1, cdc25, and chk1/2 as well as wee1, p53, and p21/cip1 (Gao et al., 2018, Chen et al., 2015a,b). Curcumin, isoflavones from soy, and garlic phytochemicals have been documented to inhibit tumor cell proliferation by decreasing cdc2 kinase activity and arresting cells at the G2-M check point (Zhang et al., 2016, 2013; Jeong et al., 2014).

Apoptosis The induction of programmed cell death has been shown to be mediated by several phytochemicals associated with G1-S and G2-M cell cycle arrest. Most of the phytochemicals

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exhibit antioxidant properties and chemoprevention against cancers (Hwang and Choi, 2015; Chikara et al., 2018). Phytochemicals affect anticancer mechanisms mediated via extrinsic and intrinsic apoptotic pathways, which both lead to the activation of downstream effector proteases (caspases) such as caspase-3 (Okubo et al., 2017; Lou et al., 2016). It has been shown that curcumin, genistein, quercetin, and tea flavonoids exerted a proapoptotic and antiproliferative effect through the downregulation of Akt, ERK, and EGFR signaling pathways and the activation of JNK signaling (Satonaka et al., 2017; Yang et al., 2018). Most of the phytochemicals also exert oxidative stress in addition to antioxidant properties. Polyphenolic compounds are known as redox modulators, which behave either as antioxidants or prooxidants depending on the microenvironment and the ROS concentration in the cell (Alrawaiq and Abdullah, 2014). Mostly, phytochemicals induce ROS production by triggering an imbalance in the redox status, which modulates the p38 MAPK and mitochondrial apoptotic pathways (Chen et al., 2017a,b). Consequently, the exposure of tumor cells to phytochemicals generates sustained ROS-mediated DNA damage that can lead to cell death via programmed cell death (Azqueta and Collins, 2016). Based on the above-mentioned data, it is clear that numerous plant extracts and phytochemicals demonstrate an inhibitory effect on signal molecules/proteins involved in cell death/survival/stress pathways.

Angiogenesis Angiogenesis, the process in which new blood vessels are formed from preexisting ones, is considered a crucial step in tumor progression. Hence, angiogenesis has become an important target for therapies directed against several cancers. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), was the first antiangiogenic drug approved by the FDA. Today, more than 10 drugs with antiangiogenic effects are in clinical use. Moreover, it was documented that some natural compounds can also block key steps in angiogenesis. In our review articles (Mojzis et al., 2008; Mirossay et al., 2018), we described the antiangiogenic effects of flavonoids and chalcones in detail. However, other nonflavonoid phenolic compounds such as gallic acid, curcumin, or resveratrol as well as natural compounds of distinctive chemical origin can also inhibit angiogenesis (Bae et al., 2006; He et al., 2016; Varinska et al., 2010; Wong and Fiscus, 2015). Furthermore, in the last decade, marine-derived compounds have been evaluated in both experimental and clinical anticancer research. Several of them were reported to also display antiangiogenic effects (Varinska et al., 2017).

Cancer stem cells There is demonstrable clinical evidence regarding treatment failure in most cancer patients due to acquired resistance. Cancer stem cells (CSCs) are characterized as a small population of cells with aggressive phenotypes present in the tumor mass. CSCs may be associated with resistance in the main treatment modalities of malignant diseases— radiotherapy, chemotherapy, or immunotherapy (Klonisch et al., 2008; Park et al., 2010;

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Soltanian and Matin, 2011). Treatment resistance in cancer includes tumor progression and maintenance, cancer recurrence, and metastases. Treatment strategies focusing on CSC targeting in an effective way are clinically important and represent a strategic way of overcoming chemoresistance. It has been documented that phytochemicals can intervene with a large amount of signaling systems in CSCs, including those sustaining the CSC self-renewal capacity and proliferation (Scarpa and Ninfali, 2015; Soltanian et al., 2018; Choi et al., 2018; Aliebrahimi et al., 2018; Liu et al., 2018). Phytochemicals represent perspective therapeutic agents for breast CSC eradication; moreover, these natural molecules may serve for the development of novel breast CSC-targeted drugs (Hermawan and Putri, 2018).

Epigenome Based on comprehensive research, it seems that epigenetic modifications are specifically important for the initiation and promotion of sporadic BC. The prediction of cancer risk in an individual is a rapidly growing area within clinical medicine. In this regard, oncology research defines specific epigenetic abnormalities, including a global methylation status of oncogenes and tumor-suppressor genes, chemical modifications of histone proteins, and the control of specific gene expression associated with noncoding RNA (Uramova et al., 2018; Khan et al., 2016). Abnormal chemical modifications of histones and altered expression of histone-modifying enzymes may be the consequence of genetic mutations in chromatin regulatory enzymes and also epigenetic modifications. Dietary phytochemicals are efficient to induce epigenetic changes and thus can be actively involved in the processes of cancer chemoprevention (Uramova et al., 2018). The role of plant-derived molecules on the methylation and acetylation of histone proteins has been described in several in vitro and in vivo studies (Altonsy et al., 2012; Attoub et al., 2011; Dagdemir et al., 2013; Collins et al., 2013). Several preclinical and clinical studies of BC demonstrated that isolated phytochemicals or their mixtures modulate the expression levels of oncogenic or tumor-suppressive miRNAs (Wang et al., 2016; Imani et al., 2017; Jung et al., 2017; Venturutti et al., 2016). It is well known that RNA epigenetic mechanisms play a substantial regulatory role in the processes of development and differentiation in cells as well as in the process of their neoplastic transformation (Uramova et al., 2018). Finally, numerous genes related to malignant disease are subject to silencing in a methylationdependent way. Hypermethylated promoters of tumor-suppressor genes manifest a significant role in carcinogenesis (Ng and Yu, 2015). A better understanding of linear and integrated signaling pathways, including miRNA expression and DNA methylation status in cancer cells, is crucial for effective therapeutic and chemoprevention approaches in clinical practice. Numerous phytochemicals represent perspective and candidate molecules for interventions into epigenetic mechanisms of carcinogenesis (Uramova et al., 2018).

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Anticancer properties of plant-derived functional foods in preclinical breast cancer research There are numerous preclinical and some clinical studies aimed at the evaluation of both anticancer activity and mechanisms of action of plant functional foods. A plethora of plant foods were evaluated to define their role in the prevention or treatment of neoplastic disease and these results may initiate a new era in cancer research.

In vitro studies Plant-based functional foods could be excellent candidates for the prevention and/or treatment of several cancers, including breast carcinoma. In this regard, our group evaluated several promising foods or herbs using an in vitro model of breast carcinoma. It includes Chlorella pyrenoidosa, young barley grass, Origanum vulgare L., Syzygium aromaticum L., and fruit peel polyphenols. Chlorella species that are rich mainly in terpenoids can be excellent candidates as functional foods due to the antioxidant, antimicrobial, antiinflammatory, and antiviral properties of bioactive compounds ( Jayshree et al., 2016; Abu-Serie et al., 2018). Our in vitro study demonstrated proapoptotic and antiproliferative effects of Chlorella pyrenoidosa in human breast adenocarcinoma cells. We have showed increased accumulation of ROS in MCF-7 cells treated with chlorella extract that was negotiated by the antioxidant Trolox. Results suggested ROS production as one of the potential proapoptotic mechanisms of chlorella treatment (Kubatka et al., 2015). In a similar in vitro study, Kunte and Desai (2018) showed that Chlorella minutissima extract successfully inhibits MMP1, -2, and -9 expressions at the mRNA as well as the protein level and inhibits MMP-2 and -9 in their active forms in the BC model. Young barley (Hordeum vulgare L.) is one of the first domesticated crops. In young barley, many different phenolic compounds have been found in extracts, including flavones (saponarin, lutonarin, 2-O-glucosylvitexin), leucoanthocyanidins, catechins, and coumarins (Meng et al., 2015). Several studies confirmed the beneficial effect of young barley extract, including anticancer activities (Zhu et al., 2015; Fang et al., 2017; Czerwonka et al., 2017; Kubatka et al., 2016a). In the BC model, Kubatka et al. (2016a) showed the caspase-dependent proapoptotic effect of young barley extract in vitro. Moreover, barley extract caused significant S-phase cell cycle accumulation, leading to apoptosis. Moreover, Woo et al. (2017) concluded that barley extract caused apoptosis of BC cells by increasing the intracellular ROS level. These results indicate a cancer chemopreventive potential of young barley as a safe dietary agent in breast carcinoma models. Possible mechanisms are still in the interests of researchers. Origanum vulgare L. is an aromatic plant known by its volatile oil rich in monoterpenoids and phenolic compounds that are associated with great antioxidant efficiency and antimicrobial capacity (Zhang et al., 2014; Vasˇko et al., 2014). The essential oil has

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well-recognized beneficial properties attributed to the high content of terpenic compounds (α-pinene, β-pinene, 1,8-cineol, menthol, linalool) or phenolic compounds such as carvacrol, eugenol, and thymol. Recently, the antiproliferative effects of a crude extract of oregano were evaluated on several cancer cell lines in vitro (Kubatka et al., 2017a; Rubin et al., 2018; Coccimiglio et al., 2016). In the BC model, Kubatka et al. (2017a) clearly showed the efficiency of oregano in the activation of caspase-7 and the inducement of apoptosis in MCF-7 cells. Furthermore, the ability of oregano to induce apoptosis is mediated through the mitochondrial apoptosis pathway by the deactivation of Bcl-2 protein activity. There are also interesting results using Origanum majorana in an in vitro BC model. The in vitro cytotoxic effect of various extracts from O. majorana was also confirmed in MDA-MB-231 BC cells (Makrane et al., 2018). Furthermore, the concentration-dependent differential effects of the extract of O. majorana were demonstrated by Al Dhaheri et al. (2013a) in the triple negative MDA-MB-231 cells. Importantly, mitotic arrest associated with a low level of DNA damage and increases in the CDK inhibitor p21 and survivin was induced by oregano extract administrated at low concentrations. On the contrary, high concentrations of oregano induced massive apoptosis mediated via the activation of the TNF-α extrinsic pathway. This pathway is associated with caspase-8 activation, a high level of DNA damage, depletion of the mutant p53, and, interestingly, deficiency in surviving proteins. O. majorana also possesses antiinvasive and antimetastatic effects against the MDA-MB-231 BC cell line. Importantly, these effects are mediated through the regulation of cellular migration, adhesion, or invasion via modulation of expression and/or the activity of various proteins, including E-cadherin, MMP-2, MMP-9, uPAR, ICAM-1, and VEGF, at least partially through inhibition of the NO and NFκB signaling pathways (Al Dhaheri et al., 2013b). These findings provide evidence of an important role of oregano as an anti-BC agent in vitro, but more attention for the further investigation of potential mechanisms is needed. Dried clove buds (Syzygium aromaticum L.) have been used as a food preservative and in traditional medicine. They are a source of a wide spectrum of bioactive compounds, including phenolic compounds (e.g., eugenol), β-caryophyllene, methyl salicylate, α-ylangene, or stigmasterol (Park and Shin, 2005). Clove attracted attention mainly due to its s-Rojas et al., 2014). However, in the last antioxidant and antimicrobial activities (Corte decade, the antiproliferative effect of clove extract or eugenol has also been studied. Our results also showed a strong antiproliferative effect of clove extract. We found that MCF-7 cells incubated with clove extract led to the accumulation of cells in the S phase shortly after 24 h. Moreover, a significant increase of cells in the sub-G0/G1 fraction was also observed. Furthermore, mitochondrial dysregulation in MCF-7 treated cells was associated with caspase activation, deactivation of Bcl-2 activity, and finally resulted in programmed cell death (Kubatka et al., 2017b). Dwivedi et al. (2011) compared the antiproliferative effectivity in five different cancer cell lines. In BC cells, the clove extract significantly inhibited the growth of both the estrogen receptor positive (MCF-7) as well as the estrogen receptor negative (MDA-MB-231) cell lines. Later, Aisha et al. (2012) confirmed the growth inhibitory effect of clove extract in both cancer cell lines.

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A lot of in vitro studies evaluated the anticancer properties of single flavonoids (Pila´tova´ et al., 2010; Kasala et al., 2016). However, several in vitro and in vivo studies documented the higher anticancer effectivity of a flavonoid combination in comparison with a single flavonoid. In our laboratories, we studied the effect of fruit peel polyphenols (Flavin7) on the growth of MCF-7 cells. We have shown a significant decrease of MCF-7 survival and arrest in the G1 phase of the cell cycle (Kubatka et al., 2016b). Later, we found that Flavin7 induced mitochondrial dysfunction followed by caspase-dependent apoptosis. Moreover, the modulation of signaling pathways such as Akt, p38 MAPK, and Erk 1/2 was also demonstrated. Furthermore, the involvement of ROS in Flavin-7 induced cell death was also clearly presented (Kello et al., 2017). Recently, the role of ROS in polyphenol-rich plant extract-induced apoptosis in BC cells was also documented by Shanmugapriya et al. (2017) and Kim et al. (2018). Both authors showed an increase in ROS production in MCF-7-treated cells associated with the activation of apoptosis machinery and cell death. Finally, there are also several other plant functional foods with documented in vitro anticancer activities against BC (Eggenschwiler et al., 2007; Harmsma et al., 2006; El Khalki et al., 2018; Hirsch et al., 2000; de Souza Grinevicius et al., 2016; Jamuna et al., 2017; Friedman et al., 2009; Staj ci  c et al., 2015) (Table 15.1).

In vivo studies Plant-derived functional foods also demonstrated anticancer effects in experimental BC models in vivo. Numerous animal studies demonstrated that plant foods significantly reduce the risk of experimental BC. Dietary-administered rosemary extract and its isolated constituent carnosol effectively inhibited 7,12-dimethyl-benz(a)anthracene (DMBA)Table 15.1

Plant-based functional foods evaluated in in vitro BC model.

FF

Cancer cells

Mistletoe

MCF-7, HCC-1937, KPL-1, MFM-223 MCF-7 MCF-7 MCF-7

Allicin

Piper nigrum

MCF-7

Piperine

Cruciferae vegetables Green tomato Tomato

MCF-7 MCF-7 MCF-7

Berberis vulgaris Garlic

FF, functional food.

Principal compounds

Main effect

Ref.

Lectins

Cytotoxicity

Berberin

block in G phase; apoptosis Cytotoxicity

Eggenschwiler et al. (2007) Harmsma et al. (2006) El Khalki et al. (2018) Hirsch et al. (2000)

Glucosinolate

G0/G1 and G2/M phase block antiproliferative Antiproliferative; cytotoxicity Antiproliferative

α-tomatine lycopene, β-carotene

Antiproliferative Antiproliferative, antioxidant

Friedman et al. (2009) Stajcic et al. (2015)

de Souza Grinevicius et al. (2016) Jamuna et al. (2017)

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induced rat mammary carcinogenesis. Compared to controls, rosemary and carnosol decreased tumor frequency per rat by 74% and 65%, respectively (Singletary et al., 1996). Moreover, rosemary and carnosol significantly reduced the in vivo formation of rat mammary DMBA-DNA adducts by 44% and 40%, when compared to controls. In another study, Jeyabalan et al. (2014) showed that blueberries (concentration 5% in the diet) reduced the tumor frequency of estradiol-mediated mammary carcinoma by 48% and 58% in female rats in prevention as well as the chemopreventive and therapeutic modes. Anticancer effects were accompanied by downregulation of CYP 1A1 and ER-α gene expression and also favorable modulation of microRNA (miR-18a and miR-34c) levels in mammary tissue. Adams et al. (2011) evaluated whole blueberry powder at two concentrations (5% and 10%) in the diet against the xenograft model of MDA-MB231 cells in female nude mice. Blueberries significantly reduced the tumor volume by 75% (5%) and 60% (10%) in animals in comparison with the controls. Moreover, mice fed 5% blueberry powder developed 70% fewer liver metastases and 25% fewer lymph node metastases compared to controls. The blueberry demonstrated significant antiproliferative activities in both treated groups and the proapoptotic mode of action after highdose therapy. In addition, the blueberry positively altered the expression of Wnt signaling, thrombospondin-2, IL-13, and IFNγ. Ravoori et al. (2012) compared the anticancer effects of blueberries and blackberries in estrogen-mediated rat mammary carcinogenesis. Compared to controls, blueberries and blackberries lengthened tumor latency by 24 and 39 days, respectively. On the other hand, the blueberry diet showed better efficacy in reducing mammary tissue proliferation and tumor frequency. Blueberries were effective in decreasing CYP1A1 expression while blackberries reduced ERα expression more effectively. Isoflavone-rich soy germ significantly decreased the occurrence of PhIP-induced mammary carcinomas in rats. Histopathological evaluations demonstrated fibrous or less malignant features of carcinomas treated with soy germ (Haba et al., 2004). Another in vivo study revealed that caraway significantly prevented and delayed rat mammary tumorigenesis induced by 17β-estradiol (Aqil et al., 2017). The authors described a reduction in tumor volume by 53% and tumor frequency by 40% in caraway-treated animals versus controls. Regarding the mechanism of action, the caraway diet significantly offset the estrogen-mediated overexpression of CYP1B1 and CYP1A1, cyclin D1, and estrogen receptor α. Bishayee et al. (2016) revealed the outstanding chemopreventive activity of a pomegranate emulsion in DMBA-induced rat mammary carcinogenesis. Pomegranate (dosing: 0.2, 1, and 5 g/kg) dose-dependently reduced tumor incidence, tumor burden, and tumor weight compared to controls. Pomegranate demonstrated apparent antiproliferative and proapoptotic activities, specifically, it (in a dose-dependent manner) increased the expression of Bad, Bax/bcl-2 ratio, caspase-3/-7/-9, poly(ADP ribose) polymerase, and cytochrome c in rat cancer tissue. In addition, the same authors (Mandal and Bishayee, 2015) demonstrated that pomegranate downregulated the expression of intratumor ER-α and ER-β and lowered the ER-α:ER-β ratio. PE also silenced Wnt signaling (via β-catenin) and cyclin D1 expression in DMBA-induced rat mammary carcinomas. In another study, Cyclopia subternata extract suppressed tumor volume to the same extent as

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tamoxifen in an orthotopic rat model of LA7 cell-induced mammary tumors. Importantly, the plant extract was not linked with the negative side effects observed with tamoxifen or letrozole in animals (Oyenihi et al., 2018). There are also several more recent papers demonstrating the anticancer activities of plant-based functional foods against experimental mammary carcinogenesis in vivo (Srinivasan et al., 2017; Nassan et al., 2018; Li et al., 2019). Recently, results from our laboratory demonstrated the chemopreventive efficacy of several plant functional foods in rat mammary carcinogenesis. Dietary-administered Origanum vulgare L. (0.1%) significantly repressed the frequency of tumors by 55.5%, suppressed tumor incidence by 44%, and decreased tumor volume by 44.5% when compared to the control group (Kubatka et al., 2017a). The evaluation of rat cancer cells showed a decrease in expression of CD24, EpCam, Ki67, and VEGFR-2. On the contrary, the expression of caspase-3 was increased after the same dose of oregano. Administration with oregano in a high dose (3%) increased the latency of tumors by 12.5 days. Furthermore, the expression of VEGFR-2, Bcl-2, CD24, and EpCam has been found to be decreased and the expression of caspase-3 has been found to be increased in in vivo carcinoma cells. Histopathological analysis demonstrated that the ratio of high-grade versus low-grade tumors was decreased in both groups administrated with oregano when compared to the control group. In another study, we analyzed the chemopreventive potential of dietary-administered Syzygium aromaticum L. (0.1% and 1%) in the same model of mammary carcinogenesis in rats (Kubatka et al., 2017b). According to our results, clove buds suppressed the frequency of tumors by 47.5% and 58.5% in a dose-dependent manner when compared to the control. Immunohistochemical analysis of rat carcinoma cells revealed that the administration of clove in higher doses was associated with a decrease in expression of Bcl-2, VEGFA, and Ki67 together with the expression of CD24 and CD44. Similarly, an expression of caspase-3, Bax, and ALDH1 was increased in the same group. Moreover, the level of MDA was considerably decreased in mammary tumors of rats in both clove groups. The analysis of histone modifications revealed an increase in lysine trimethylations and acetylations (H4K20me3, H4K16ac) in carcinomas after oregano treatment. The total promoter methylation status of TIMP3 and RASSF1A genes did not show any significant changes after clove administration in rats. Our experiment with dark fruit peels (0.3% and 3% in the diet) showed that a high-dose lyophilized substance decreased the tumor frequency by 58% when compared with the control group. Moreover, the tumor incidence was also found to be decreased by 24% and latency was lengthened by 8 days in the high-dose group compared with the control. Chemoprevention significantly decreased the ratio of high-grade and low-grade carcinomas in the high-dose group. Additionally, results from the analysis of rat carcinoma cells showed that the high-dose intake of dark fruit peels was associated with an increase in the expression of caspase-3 and a decrease in the expression of Bcl-2, Ki67, and VEGFR-2 (Kubatka et al., 2016b). Moreover, we tested two “green foods”—Chlorella pyrenoidosa and young barley grass—in the same rat BC model (doses of 0.3% and 3% in the diet). Chlorella at a higher dose suppressed tumor frequency by 61% and lengthened tumor latency by 12.5 days in comparison with

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the controls (Kubatka et al., 2015). An evaluation of the mechanism of anticancer action showed that caspase-7 expression increased by 73.5% and vascular endothelial growth factor receptor-2 expression decreased by 19% in rat tumor cells in the high-dose chlorella group. Barley (0.3%) revealed only a mild antitumor effect in mammary carcinogenesis, and a higher barley dose did not further improve this effect. Immunohistochemical analysis of rat tumor cells demonstrated an increase in caspase-3 expression and a reduction in Ki67 expression in both treated groups. In addition, barley (3%) demonstrated antioxidant effects by decreasing dityrosine levels versus control (Kubatka et al., 2016a). Our most recent results with Thymus vulgaris L. manifested significant suppression of rat mammary carcinoma multiplicity after chemoprevention. Moreover, thyme showed substantial and beneficial epigenetic effects on the methylation status of four gene promoters (ATM, RASSF1, PTEN, and TIMP3), histone chemical modifications (H3K4m3), and miRNA expression in tumor cells (miR22, miR34a, and miR210) (Kubatka et al., 2019). Oregano, cloves, fruit peels, chlorella, young barley, and thyme demonstrated significant beneficial effects on the plasma lipid metabolism in rats (Kubatka et al., 2015, 2016a, b, 2017a,b). Table 15.2 summarizes the in vivo BC studies evaluating the tumor-suppressive effects of plant functional foods.

Epidemiological and clinical breast cancer studies The potential importance of nutrition and diet in cancer prevention or treatment is recognized due to the great amount of evidence from either laboratory or epidemiological and clinical research. Unfortunately, dietary recommendations for cancer prevention are not well integrated into preventive practice (Mayne et al., 2016). However, diet can play a key role in the reduction of cancer incidence (Stepien et al., 2016). A metaanalysis of 13 epidemiological studies (11 case-control and two cohort studies) suggested that a high intake of cruciferous vegetables may lower the risk of BC (RR 0.85, 95% CI 0.77–0.94) (Liu and Lv, 2013). The association between the consumption of berries and peaches/nectarines and the risk of ER- postmenopausal BC was evaluated among women included in the Nurses’ Health Study. Eventually, lower risk of ER-breast cancer was related to higher intake of specific fruits when compared with nonconsumers. The multivariate RR associated with consumption of total berries every two servings per week was 0.82 (95% CI 0.71–0.96, P ¼ 0.01) and 0.69 (95% CI 0.50–0.95, P¼ 0.02) for consuming at least one serving of blueberries per week when compared with nonconsumers. Furthermore, the consumption of at least two portions of nectarines or peaches weekly was associated with RR 0.59 (95% CI ¼ 0.37–0.93, P ¼ 0.02) (Fung et al., 2013). Moreover, a cohort study in which postmenopausal Singapore Chinese women were included suggested the anticancer effects of a vegetable-fruit-soy diet. A greater intake of a diet characterized by cruciferous vegetables, fruits, and soy demonstrated a dose-dependent trend of decreasing postmenopausal BC risk (HR 0.70, 95% CI 0.51, 0.95) for the fourth quartile compared with the first one. Importantly, a stronger association was demonstrated between postmenopausal women and a diet rich in vegetables, fruits, and soy with 5 year of follow-up (HR 0.57, 95% CI

Chapter 15 • Effects of plant-derived functional foods in mammary carcionogenesis

Table 15.2

Plant-based functional foods (FF) in an animal breast cancer model.

FF

Model

Dosage

Rosemary

DMBA-induced MC in rats Estradiolinduced MC in rats MDA-MB-231 in nude mice

200 mg/kg body wt (i.p.) 5% in the diet

Estrogenstimulated MC in rats PhIP-induced MC in rats Estrogenmediated MC in rats DMBA-induced MC in rats

5% in the diet

Blueberries

Blueberries

Blueberries or Blackberries Soya germ Caraway

Pomegranate

5% or 10% in the diet

– 7.5% in the diet

0.2–1.0–5.0 g/kg

orthotopic model of LA7 cell-induced MC DMBA-induced MC in rats DMBA-induced MC in rats

100, 200, 300, 500 mg/kg

Chlorella pyrenoidosa Young barley (grass) Mixture of fruit peel polyphenols

NMU-induced MC in rats NMU-induced MC in rats NMU-induced MC in rats

3 g/kg or 30 g/kg of chow 3 g/kg or 30 g/kg of chow 3 g/kg or 30 g/kg of chow

Origanum vulgare L. (haulm)

NMU-induced MC in rats

3 g/kg or 30 g/kg of chow

Cyclopia subternata Dunaliella salina Taraxacum officinale

1000 mg/kg 500 mg/kg

Anticancer effects/Mechanism of action # Tumor frequency, # formation of DMBA-DNA adducts # Tumor frequency, # expression of CYP1A1 and ERα, modulation of miR-18a and miR-34c # Tumor volume, # liver and lymph node metastases, # proliferation, " apoptosis " Tumor latency, # tumor frequency, # proliferation, # expression of CYP1A1 and ERα # Tumor incidence, improved histopathology of tumors " Tumor latency, # tumor frequency and volume, # expression of CYP1A1, CYP1B1, cyclinD1 and ERα # Tumor incidence, burden and weight, " Bad, " Bax/bcl-2 ratio, " caspase-3/-7/-9, " poly(ADP ribose) polymerase, " cytochrome c, # expression of ERα and ERβ, # Wnt signalling and cyclin D1 expression # Tumor volume

# Tumor frequency, # proliferation, " apoptosis # Levels of CA15-3, # expression of Pdk1, Akt1, Map3k1, Erbb2, and PIk3ca, # proliferation and Bcl-2 expression # Tumor frequency, " tumor latency, " apoptosis " Apoptosis, # proliferation, # protein oxidation # Tumor frequency and incidence, " tumor latency, improved histopathology of tumors, " apoptosis, # proliferation, # angiogenesis # Tumor frequency and volume, " tumor latency, improved histopathology of tumors, " apoptosis, # proliferation, # angiogenesis, # lipid oxidation, anti-BCSCs effects

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Ref. Singletary et al. (1996) Jeyabalan et al. (2014) Adams et al. (2011)

Ravoori et al. (2012)

Haba et al. (2004) Aqil et al. (2017)

Mandal and Bishayee (2015), Bishayee et al. (2016)

Oyenihi et al. (2018)

Srinivasan et al. (2017) Nassan et al. (2018)

Kubatka et al. (2015) Kubatka et al. (2016a) Kubatka et al. (2016b)

Kubatka et al. (2017a)

Continued

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Table 15.2

Plant-based functional foods (FF) in an animal breast cancer model—cont’d

FF

Model

Dosage

Syzygium aromaticum L. (cloves)

NMU-induced MC in rats

1 g/kg or 10 g/kg of chow

Anticancer effects/Mechanism of action # Tumor frequency, " apoptosis, # proliferation, # angiogenesis, # lipid oxidation, positive epigenetic modulation

Ref. Kubatka et al. (2017b)

DMBA, 7,12-dimethylbenz(a)anthracene; MC, mammary carcinogenesis; NMU, N-methyl-N-nitrosourea.

0.36, 0.88, P for trend 1–2 weeks (strength of recommendation: strong; level of evidence: very low). Nutraceuticals or Pharmaconutrients improve the immune and metabolic functions in malnourished patients with advanced cancer and cachexia.  The fish-derived omega-3 polyunsaturated fatty acids (2 g/day) in advanced cancer patients receiving chemotherapy can improve appetite, energy intake, body weight, muscle mass, and/or physical activity (strength of recommendation: weak; level of evidence: low).  The enteral and oral immunonutrition (a combination of arginine, nucleotides, and omega-3) is the choice to reduce postoperative infectious complications in indoor cancer patients with upper gastrointestinal tract surgery (strength of recommendation: strong; level of evidence: high).  The branched-chain amino acids (leucine or hydroxymethylbutyrate (HMB), glutamine-arginine-HMB) can be supplemented to increase muscle mass (patients without mucositis/enteritis, hematopoietic cell transplant). Consider the administration of enteral arginine to reduce the incidence of fistulae for head and neck cancer survivors. Consider interventions based on the cancer treatment given and the stage of neoplastic disease. We recommend the Enhanced Recovery After Surgery (ERAS) program to lessen surgical stress, minimize catabolism, maintain nutritional status, reduce complications, and optimize recovery better and faster in curative or palliative surgery (strength of recommendation: strong; level of evidence: high). The nutritional

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components of ERAS are avoiding preoperative fasting, preoperative carbohydrate treatment, reestablishment of oral feeding on the first postoperative day, and early mobilization. Use this program to screen for malnutrition and suggest nutrition support to survivors at risk. Consider a thorough nutritional assessment, individualized nutritional counseling, and, if necessary, oral nutritional supplements to improve nutritional intake, body weight, and quality of life. This could enable patients to avoid radiation treatment options to GIT or head/neck cancer survivors (strength of recommendation: strong; level of evidence: moderate). Consider oral feeding to patients with inadequate food intake because enteral feeding reduces weight loss, treatment interruptions, and rehospitalizations compared to oral feeding. Consider nasogastric tube feeding or gastrostomy (prophylactic tube feeding) in cases of hypopharyngeal tumor T4, or combined radiochemotherapy to improve weight loss, and quality of life while decreasing rehospitalization and treatment interruptions. In severe mucositis or in obstructive tumors of the head, neck, or thorax, enteral feeding is recommended using nasogastric or gastrostomy tubes (strength of recommendation: strong; level of evidence: low). Consider a home PN over surgery in chronic radiation enteritis that evolves into intestinal failure. Rule out any gastrointestinal reason for intestinal failure before PN is the choice. Consider PN if adequate oral/enteral nutrition is not possible (severe radiation enteritis or malabsorption) (strength of recommendation: strong; level of evidence: moderate). Consider carefully the targeted therapies (particularly multikinase inhibitors) prior to chemotherapy for cancer survivors as targeted therapies cause weight loss and low muscle mass (muscle wasting) with increased risk of toxicity, worse performance status, impaired quality of life, and shorter survival. Consider weight stabilization in gastrointestinal and lung cancer patients to increase survival by dietary counseling and/or oral nutritional supplements (sufficient proteins, vitamins, and minerals) to improve nutritional intake and quality of life as well as keep a stable body weight. During anticancer drug treatment, consider dietary counseling for oral nutritional supplements to frank malnutrition and patients with decreased oral intake (strength of recommendation: strong; level of evidence: moderate). However, the use of enteral or parenteral nutrition in all cancer patients receiving cytotoxic therapy may not show any beneficial effect on survival. Patients with advanced cancer receiving no anticancer treatment show worse quality of life and performance status. Consider nutrition support, taking into account these patient’s expected survival, nutritional status, potential benefits, and the expectations

Chapter 21 • Food and nutrition in cancer survivors: LONGLIVE lifestyle





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and wishes of both the patient and their close relatives in the last weeks of life or possible further life. We recommend mandatory screening of nutritional status of all survivors before