Reviews of Physiology, Biochemistry and Pharmacology 176 [1st ed.] 978-3-030-14026-7;978-3-030-14027-4

Table of contents :
Front Matter ....Pages i-v
DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases (Lucas Falcão Monteiro, Pault Yeison Minaya Ferruzo, Lilian Cristina Russo, Jessica Oliveira Farias, Fábio Luís Forti)....Pages 1-35
Oncotic Cell Death in Stroke (Kep Yong Loh, Ziting Wang, Ping Liao)....Pages 37-64
Magnesium Extravaganza: A Critical Compendium of Current Research into Cellular Mg2+ Transporters Other than TRPM6/7 (Martin Kolisek, Gerhard Sponder, Ivana Pilchova, Michal Cibulka, Zuzana Tatarkova, Tanja Werner et al.)....Pages 65-105
Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and Radiotherapy-Associated Resistance (Amir Abbas Momtazi-Borojeni, Jafar Mosafer, Banafsheh Nikfar, Mahnaz Ekhlasi-Hundrieser, Shahla Chaichian, Abolfazl Mehdizadehkashi et al.)....Pages 107-129
Correction to: Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and Radiotherapy-Associated Resistance (Amir Abbas Momtazi-Borojeni, Jafar Mosafer, Banafsheh Nikfar, Mahnaz Ekhlasi-Hundrieser, Shahla Chaichian, Abolfazl Mehdizadehkashi et al.)....Pages 131-131

Citation preview

Reviews of Physiology, Biochemistry and Pharmacology 176

Reviews of Physiology, Biochemistry and Pharmacology

More information about this series at http://www.springer.com/series/112

Bernd Nilius
Pieter de Tombe
Thomas Gudermann
Reinhard Jahn
Roland Lill Editors

Reviews of Physiology, Biochemistry and Pharmacology 176

Editor in Chief Bernd Nilius Department of Cellular and Molecular Medicine KU Leuven Leuven, Belgium Editors Pieter de Tombe Heart Science Centre The Magdi Yacoub Institute Harefield, United Kingdom Reinhard Jahn Department of Neurobiology Max Planck Institute for Biophysical Chemistry Go¨ttingen, Germany

Thomas Gudermann Walther-Straub Institute for Pharmacology and Toxicology Ludwig-Maximilians University of Munich Munich, Germany Roland Lill Department of Cytobiology University of Marburg Marburg, Germany

ISSN 0303-4240 ISSN 1617-5786 (electronic) Reviews of Physiology, Biochemistry and Pharmacology ISBN 978-3-030-14026-7 ISBN 978-3-030-14027-4 (eBook) https://doi.org/10.1007/978-3-030-14027-4 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases . . . Lucas Falc~ao Monteiro, Pault Yeison Minaya Ferruzo, Lilian Cristina Russo, Jessica Oliveira Farias, and Fa´bio Luı´s Forti Oncotic Cell Death in Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kep Yong Loh, Ziting Wang, and Ping Liao Magnesium Extravaganza: A Critical Compendium of Current Research into Cellular Mg2+ Transporters Other than TRPM6/7 . . . . Martin Kolisek, Gerhard Sponder, Ivana Pilchova, Michal Cibulka, Zuzana Tatarkova, Tanja Werner, and Peter Racay Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and Radiotherapy-Associated Resistance . . . . . Amir Abbas Momtazi-Borojeni, Jafar Mosafer, Banafsheh Nikfar, Mahnaz Ekhlasi-Hundrieser, Shahla Chaichian, Abolfazl Mehdizadehkashi, and Atefeh Vaezi Correction to: Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and Radiotherapy-Associated Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amir Abbas Momtazi-Borojeni, Jafar Mosafer, Banafsheh Nikfar, Mahnaz Ekhlasi-Hundrieser, Shahla Chaichian, Abolfazl Mehdizadehkashi, and Atefeh Vaezi

1

37

65

107

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Rev Physiol Biochem Pharmacol (2019) 176: 1–36 DOI: 10.1007/112_2018_12 © Springer Nature Switzerland AG 2018 Published online: 2 August 2018

DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases Lucas Falcão Monteiro, Pault Yeison Minaya Ferruzo, Lilian Cristina Russo, Jessica Oliveira Farias, and Fábio Luís Forti

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Protein Tyrosine Phosphatase (PTP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Dual-Specificity Phosphatase (DUSP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 ADUSP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 DUSP3/VHR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Molecular and Biological Functions of DUSP3/VHR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 DUSP3 in Tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 DUSP3 in Genomic Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 DUSP3 in Blood-Associated Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Overview of Current Knowledge on DUSP3/VHR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 3 4 6 6 8 8 12 15 17 28 29

Abstract Protein tyrosine kinases (PTK), discovered in the 1970s, have been considered master regulators of biological processes with high clinical significance as targets for human diseases. Their actions are countered by protein tyrosine phosphatases (PTP), enzymes yet underrepresented as drug targets because of the high homology of their catalytic domains and high charge of their catalytic pocket. This scenario is still worse for some PTP subclasses, for example, for the atypical dual-specificity phosphatases (ADUSPs), whose biological functions are not even completely known. In this sense, the present work focuses on the dual-specificity phosphatase 3 (DUSP3), also known as VH1-related phosphatase (VHR), an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 expression and activities are suggestive of a tumor suppressor or tumorpromoting enzyme in different types of human cancers. Furthermore, DUSP3 has other biological functions involving immune response mediation, thrombosis, hemostasis, angiogenesis, and genomic stability that occur through either MAPKL. F. Monteiro, P. Y. M. Ferruzo, L. C. Russo, J. O. Farias, and F. L. Forti (*) Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil e-mail: fl[email protected]

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dependent or MAPK-independent mechanisms. This broad spectrum of actions is likely due to the large substrate diversity and molecular mechanisms that are still under scrutiny. The growing advances in characterizing new DUSP3 substrates will allow the development of pharmacological inhibitors relevant for possible future clinical trials. This review covers all aspects of DUSP3, since its gene cloning and crystallographic structure resolution, in addition to its classical and novel substrates and the biological processes involved, followed by an update of what is currently known about the DUSP3/VHR-inhibiting compounds that might be considered potential drugs to treat human diseases. Keywords Dual-specificity phosphatase 3 (DUSP3) · Mitogen-activated protein kinases (MAPK) · Pharmacological DUSP3 inhibitors · Phosphatases on human diseases · Protein tyrosine phosphatases (PTP) · Vaccinia H1-related phosphatase (VHR)

1 Introduction In recent years there has been substantial progress in the development of protein tyrosine phosphatase (PTP) inhibitors suggesting that these enzymes, for long time considered undruggable, can provide unique solutions for the treatment of human diseases (Hendriks et al. 2013; Tonks 2013). Many recent strategies have been used in the development of drugs that target PTPs as ways of expanding the possibilities of intervention in the function of these enzymes and in biological processes dependent on them. These strategies include (a) orthosteric inhibitors (reversible competitive, bidentate or uncompetitive, and irreversible), (b) allosteric inhibitors, (c) oligomerization inhibitors, (d) radioimmunotherapy, and (e) PTP receptor biological decoy (He et al. 2013; Stanford and Bottini 2017). The continuous generation of more selective probes of high quality for the activity of individual PTPs is essential for the successful development of inhibitory drugs of these enzymes. New chemical inhibitors are enhancing performance in PTPs already considered clinical targets such as PTP1B and SHP-2 and are bringing into focus new targets such as STEP, PTPN22, VE-PTP, CD45, CDC25A/B/C, and LMPTP. Advances of functional studies of RPTPs are revealing new opportunities for inhibiting PTP domains within the receptor structure using small biological molecules that act to stabilize the oxidation of catalytic intermediates or even the formation of receptor complexes. But, there are no magic bullets to attack the PTPs, and a successful strategy for an enzyme from one of the classes may not be as effective for a member of another class or even for a different member of the same class (He et al. 2013; Stanford and Bottini 2017). This is the case, for example, of the dual-specificity phosphatases (DUSPs), which have a diversity of structural possibility of substrates, many of which have not yet been identified both structurally and functionally (Tonks 2013). Among the members of this subclass I of PTPs (Fig. 1), DUSP6 and PRL-1/2/3 are being considered druggable targets for some deficiencies of the immune system, including

DUSP3/VHR Is a Potential Drug Target

3

Fig. 1 A brief classification of the protein tyrosine phosphatase (PTP) superfamily within the human genome showing the numerical distribution in the four classes and highlighting the DUSP3 belonging to the atypical dual phosphatases

cancer, and also for melanomas (Stanford and Bottini 2017). This review has as differential a specific focus on DUSP3, aiming to enlarge the list of druggable targets of the atypical dual phosphatases (He et al. 2013; Hendriks et al. 2013). We first describe all its molecular targets and biological functions described in the literature; and, secondly, we reexamine all inhibitors already developed and discuss their mechanism of action, specificity, permeability, bioavailability, and potential as a drug or as a starting point for drug development.

2 Protein Tyrosine Phosphatase (PTP) PTPs are very specific, non-redundant, and catalytically active enzymes. While protein tyrosine kinases (PTKs) constitute a superfamily of enzymes with the same evolutionary origin, PTPs have distinct evolutionary origins (Alonso et al. 2004c;

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Manning et al. 2002; Vang et al. 2008). PTPs are classified into four subfamilies according to amino acid sequences that share their catalytic domain and according to the presence of cysteine (Cys or C) or aspartate (Asp or D) in the catalytic cleft that acts as a catalytic amino acid. PTPs expression patterns vary; there are enzymes with wide distribution and some are specific to certain tissues. Most human cells express 30–60% of all the PTPs genes; neural and hematopoietic cells commonly express more PTPs than other tissues (Vang et al. 2008). Three subfamilies (classes I–III) present cysteine-based catalysis, and together, they make up almost all of the PTPs, comprising 99 proteins (Fig. 1). Class I is subdivided into both classical tyrosine phosphatases and dual phosphatases, which are the more diversified phosphatases that dephosphorylate not only the tyrosine (Tyr) residue (Alonso et al. 2004c). Class II is also Tyr-specific, and its only representative is the low molecular weight protein Tyr phosphatase (LMWPTP), a highly conserved evolutionary enzyme that may have broad implications for human health (Patterson et al. 2009). Class III differs from the others by the presence of a rhodanese structure. It is composed of cell cycle regulatory proteins, cell division cycle 25 (Cdc25) phosphatases, which activate cyclin-dependent kinases (CDKs) when they remove phosphate pools from some Tyr and Thr residues present in their regulatory sites (Mustelin 2007). The fourth and last subfamily (Class IV) is formed by phosphatases that have aspartate as a critical residue in the catalytic cleft: (1) EyA (eyes absent) proteins play an important role in the organogenesis of vertebrates, and (2) haloacid dehalogenase (HAD) proteins are able to dephosphorylate both Tyr and Ser/Thr residues from various substrates, including proteins, sugars, nucleotides, and phospholipids (Fig. 1) (Bayón and Alonso 2010; Mustelin 2007; Patterson et al. 2009).

2.1

Dual-Specificity Phosphatase (DUSP)

The dual-specificity phosphatase (DUSP) group is the largest and most diversified among the nonclassical PTPs and is composed of 61 proteins (Fig. 1). DUSPs are able to dephosphorylate both Tyr and Ser/Thr residues due to their catalytic site’s structure, which is not as deep as and more open than that of classical phosphatases. The consensus sequence, HC(X)5R, present in the catalytic domain of classical phosphatases and DUSPs, is highly conserved. At the base of the catalytic cleft is the Cys residue, which characterizes classes I–III (Alonso et al. 2004c; Farooq and Zhou 2004; Mandl et al. 2005). DUSP’s catalytic mechanism and that of classical phosphatases are similar and involve substrate hydrolysis and formation of a stable phosphoryl intermediate, with an arginine residue near the catalytic slit contributing directly to the reaction catalysis; a slightly distant aspartate acid protonates the phosphate group (Fig. 2) (Bayón and Alonso 2010; Denu and Dixon 1995, 1998). The DUSP subfamily has diverse biological roles as evidenced by its subdivision into 16 groups. It has been well established that it is involved in mitogen-activated protein kinase (MAPK) pathway regulation, acting mainly on extracellular-regulated

DUSP3/VHR Is a Potential Drug Target

5

Fig. 2 Details of the DUSP3/VHR crystal structure presenting the four amino acid residues more relevant to its enzymatic activity. (a) The catalytic cysteine (Cys) 124 (yellow) is shown in close proximity to histidine (His) 123 and arginine (Arg) 130 residues (red) comprising the catalytic triad. (b) The regulatory tyrosine (Tyr) 138 (green) is sitting at a central alpha helix, relatively distant from the catalytic cysteine (yellow) (modified from 1vhr.pdb) (Yuvaniyama et al. 1996)

kinase (ERK)1/2, jun kinase (JNK), and p38 (Bayón and Alonso 2010; Bermudez et al. 2010; Nunes-Xavier et al. 2011; Patterson et al. 2009; Pulido and Hooft van Huijsduijnen 2008). In this context, DUSP subfamily members play important roles in several cell events: (1) in cell cycle regulation, a function usually performed by the MAPK phosphatases (MKPs, including PAC1, MKP1–5, MKP7, hVH3, hVH5, PYST2, and MK-STYX) and some other atypical DUSPs, including DUSP3, the protein of interest in this work (Nunes-Xavier et al. 2011; Patterson et al. 2009; Pulido and Hooft van Huijsduijnen 2008), (2) in several types of cancer (MKPs1–3, MKP8, PAC1, DUSP3 and 5, PTEN, and PRLs) (Arnoldussen and Saatcioglu 2009; Bermudez et al. 2010; Nunes-Xavier et al. 2011; Pulido and Hooft van Huijsduijnen 2008), (3) in immune responses and inflammation (MKP1, 5, and 6, PAC1, and DUSP3) (Jeffrey et al. 2007; Lang et al. 2006; Salojin and Oravecz 2007), and (4) hereditary diseases (MTM and Laforin) (Bayón and Alonso 2010; Patterson et al. 2009; Pulido and Hooft van Huijsduijnen 2008). DUSP subgroups are organized according to shared sequence similarity and by the presence of specific structures; for example, the MKPs have the CDC25 homology 2 (CH2) at their N-terminal, while the myotubularins (MTM) present a pleckstrin homology (PH) domain at its N-terminus, which explains the activity of MTM on lipids (Bermudez et al. 2010; Nunes-Xavier et al. 2011; Patterson et al. 2009). The less characterized and even more diversified subgroup are the small (generally Co2+ > Mg2+ ≥ Mn2+ ≥≥ Sr2+ ≥ Cd2+ ≥ Ca2+

Mrs2

Px/PMg (Sc): Mg2+ > Ni2+ NT (not transported): Ca2+, Mn2+, Co2+ Px/PMg (Mm): Mg2+ > Sr2+ ≈ Fe2+ > Ba2+ > Cu2+ > Zn2+ ≈ Co2+ > Cd2+ > Mn2+ NT: Ni2+, Ca2+, Gd3+ Px/PMg (Mm): Ba2+ > Mg2+ > Ni2+ ≈ Zn2+ > Sr2+ ≈ Fe2+ > Mn2+ > Cu2+ ≈ Co2+ NT: Ca2+, Cd2+ Px/PMg (Mm): Mg2+ > Ba2+ > Ni2+ > Co2+ > Sr2+ ≈ Fe2+ > Mn2+ NT: Ca2+, Cu2+, Zn2+, Cd2+ (Mm) Highly selective for Mg2+

SLC41A1 SLC41A3a SLC41A2 MagT1 TUSC3/N33 a NIPA1 NIPA2

Citation Voets et al. (2004) Penner and Fleig (2007) and Monteilh-Zoller et al. (2003) Schindl et al. (2007) Quamme (2010) and Goytain and Quamme (2005a) Quamme (2010) Quamme (2010) and Goytain and Quamme (2005b)

Px/PMg (Mm): Mg2+ > Mn2+ > Cu2+ > Fe2+ > Ba2+ ≈ Co2+ > Sr2+ ≈ Zn2+ ≥ Ni2+ > Ca2+ Px/PMg (Mm): Mg2+ > Sr2+ > Co2+ > Zn2+ ≈ Fe2+ > Ni2+ ≈ Ca2+ ≈ Ba2+ ≈ Cu2+ ≈ Mn2+ NT: Cd2+ Px/PMg (Mm): Mg2+ Sr2+ ≈ Co2+ ≈ Zn2+ ≈ Fe2+ ≈ Cd2+ ≈ Ni2+ ≈ Ca2+ ≈ Ba2+ ≈ Cu2+ ≈ Mn2+ 2+

NPAL3

Px/PMg (Mm): Mg >

NPAL4/Ichthyin MMgT1

Px/PMg (Mm): Mg2+ > Ba2+ > Sr2+ > Fe2+ > Cu2+ ≈ Ca2+ ≈ Zn2+ ≥ Co2+ ≈ Mn2+ ≈ Ni2+ NT: Cd2+ Px/PMg (Mm): Mg2+ ≥ Sr2+ ≥ Fe2+ > Co2+ > Cu2+ > Ba2+ > Ca2+ > Zn2+ > Mn2+ > Ni2+

MMgT2

Px/PMg (Mm): Mg2+ ≥ Sr2+ > Ba2+ > Cu2+ > Mn2+ > Co2+ > Ni2+ > Fe2+ > Zn2+ ≥ Ca2+

CNNM2

Px/PMg (Mm): Mg2+ ≥ Co2+ > Ba2+ ≥ Mn2+ ≈ Gd3+ ≥ Sr2+ > Cu2+ ≥ Fe2+ NT: Zn2+, Cd2+, Ni2+, Ca2+ The permeation profile in original paper (Goytain and Quamme 2005d) does not match the permeation profile published in review (Quamme 2010) Px/PMg: not available Px/PMg (Mm): Mg2+ > Fe2+ > Cu2+ > Co2+> Ni2+ > Ca2+ NT: Sr2+, Ba2+, Mn2+, Zn2+, Cd2+ Px/PMg: not available Px/PMg (Mm): Mg2+ ≈ Sr2+ > Ni2+ > Ba2+ > Zn2+ ≥ Mn2+ > Fe2+ NT: Co2+, Cu2+, Ca2+ Px/PMg (Mm): Mg2+ ≈ Sr2+ > Ni2+ ≥ Mn2+ > Cu2+ ≈ Ba2+ ≈ Zn2+ NT: Fe2+, Co2+, Ca2+

CNNM1 CNNM3a CNNM4 HIP14 HIP14L

Sr2+

>

Ba2+ > Fe2+

≈

Mn2+

>

Cu2+

≈

Co2+

>

Zn2+

≈

Cd2+

>

Ni2+

≈

Ca2+

Quamme (2010) and Goytain and Quamme (2005c) Quamme (2010) Quamme (2010) and Goytain et al. (2007, 2008a) Quamme (2010) and Goytain et al. (2008a) Quamme (2010) and Goytain et al. (2008a) Quamme (2010) and Goytain et al. (2008a) Quamme (2010) and Goytain and Quamme (2008) Quamme (2010) and Goytain and Quamme (2008) Quamme (2010) and Goytain and Quamme (2005d)

Quamme (2010)

Quamme (2010) and Goytain et al. (2008b) Quamme (2010) and Goytain et al. (2008b)

a

Indicates that the data were introduced in the review paper and not in original research paper. Please note that the npMgT permeation profiles were reconstructed mostly from the graphical content published in indicated papers of the group around Quamme (green) (Quamme 2010; Goytain and Quamme 2005a, b, c, d, 2008; Goytain et al. 2007, 2008a, b). Due to frequent lack of statistics in the original works, it is not being reflected in our interpretation of these permeation profiles

transporter (mammalian/murine in the case of npMgTs). If the transporter builds functional complexes with another proteins and/or factors that play essential roles in the maintenance/regulation of its normal physiological function, and if these proteins/factors are not present in X. laevis oocytes, then the transporter might act in a mode different (deviated) from its normal function or it might be completely dysfunctional (Goldin 2006). Of note, the principles of TEV do not allow the establishment of a true permeation profile of any transporter/channel because of the lack of any control for the intracellular ion milieu (Kolisek et al. 2008; Goldin 2006; Fleig et al. 2013). Considering latter, the functional data concerning npMgTs as acquired with TEV in X. laevis oocytes must thus be interpreted cautiously. Further verification/examination of these data in homologous expression systems with appropriate electrophysiological techniques should therefore be carried out.

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3 Expression Profiles of Novel Magnesiotropic Genes and Their Protein Products The expression profiles of the novel magnesiotropic genes in various human organs or tissues are summarized in Table 3. At the level of mRNA, the majority of the novel magnesiotropic genes are expressed in most of the tested organs/tissues (Table 3). A ubiquitous and/or almost ubiquitous expression of MgGs might indicate their importance for overall cellular physiology. However, at the protein level, TRPM6, CNNM1, CNNM4, NIPAL4, HIP14, and HIP14L are only detected in specific organs/tissues that have absorptive functions, re-absorptive functions, barrier functions, or secretory functions, or in those that are metabolically highly active (https://www.proteinatlas.org) (Romani 2011; Quamme 2010).

4 Cellular Compartmentalization and Functional Characterization of Proteins Encoded by the Putative and Confirmed Mg2+ Transporters/Mg2+ Homeostatic Factors All proteins encoded by the novel MgGs possess membrane-spanning α-helices in their structures, and thus, all are expected to reside in the cytoplasmic membrane or in the membranes of intracellular compartments. In general every cell type is assumed to possess plasma membrane transporters allowing the influx of Mg2+ and transporters that mediate its efflux (Nishizawa et al. 2007; Romani 2011). In particular, the simultaneous presence of both Mg2+ influxand Mg2+ efflux-mediating transport systems is of eminent importance in Mg2+ absorptive and re-absorptive epithelia (Nishizawa et al. 2007; Romani 2011; de Baaij et al. 2015; Schweigel et al. 1999, 2000, 2006, 2009; Schweigel and Martens 2003). In cells that transport Mg2+ via the transcellular pathway, a clear polarized distribution has been demonstrated for influx- and efflux-mediating Mg2+ transport mechanisms. For example, the apical membrane of ruminal epithelial cells (REC) contains primarily influx-mediating Mg2+ transport mechanisms, whereas the basolateral membrane contains primarily Mg2+ efflux-mediating transport mechanisms (Schweigel et al. 1999, 2000; Schweigel and Martens 2000). In non-polarized cells, both influx and efflux mechanisms are assumed to be present in the cytoplasmic membrane but with no clearly traceable pattern of their distribution (Nishizawa et al. 2007; Romani 2011). Furthermore, the cells conducting the transcellular transport of Mg2+ must contain mechanism(s) that sort(s) the pool of the total cellular Mg2+ into two smaller pools; the first is intended for transcellular transport, and the second is intended for the use of the cells themselves. This mechanism(s) must be regulated and at the same time, very flexible. The existence of such mechanism(s) is only possible in the

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Table 3 Organ/tissue-specific expression of confirmed and putative human magnesiotropic genes according to www.proteinatlas.org Gene TRPM6

RNA detected in (HPA, GTEx, FANTOM5) Ubiquitous with the highest expression level in colon, kidney

TRPM7 Mrs2 SLC41A1 SLC41A3 SLC41A2 MagT1 NIPA1/ SLC57A1 NIPA2/ SLC57A2 NIPAL3 NIPAL4

Ubiquitous Ubiquitous Ubiquitous Ubiquitous Ubiquitous Ubiquitous Ubiquitous with the highest expression level in brain Ubiquitous

TUSC3/ N33

Almost ubiquitous with the highest expression level in brain and urogenital tract Ubiquitous Ubiquitous Ubiquitous with the highest level of expression in brain, kidney, and testis Brain, testis Ubiquitous Ubiquitous with the highest level of expression in brain, colon, rectum, small intestine Almost ubiquitous with the highest expression level in brain Almost ubiquitous with the highest expression level in brain Data not available Ubiquitous Ubiquitous Ubiquitous Cerebral cortex, cerebellum, testis Brain, lungs, thyroid glands, esophagus, skin, epididymis, breast Ubiquitous

MMgT1 MMgT2 CNNM2/ ACDP2 CNNM1 CNNM3 CNNM4

ZDHHC17/ HIP14 ZDHHC17/ HIP14L MagC1 SLC25A24 SLC25A25 SLC25A23 SLC25A41 ATP13A4 ATP13A2 (PARK9) XK

Ubiquitous Ubiquitous

Ubiquitous (low levels); enhanced expression in small intestine

Protein detected in Colon, rectum, small intestine, duodenum, parathyroid gland, kidney, testis Ubiquitous Ubiquitous Ubiquitous Ubiquitous Almost ubiquitous Almost ubiquitous Almost ubiquitous Almost ubiquitous Almost ubiquitous Parathyroid gland, adrenal gland, liver, gastrointestinal tract, testis, placenta, skin Ubiquitous

Ubiquitous Data not available Ubiquitous Brain, kidney, testis, skin Ubiquitous Not ubiquitous, the highest level in brain, stomach, small intestine, colon, rectum Not ubiquitous, the highest level in brain and urogenital tract Not ubiquitous, the highest level in stomach and testis Data not available Almost ubiquitous Almost ubiquitous Almost ubiquitous Inconclusive data set Inconclusive data set Ubiquitous Almost ubiquitous (low levels)

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presence of (a) intracellular compartments dedicated to the storage of Mg2+ (intracellular Mg2+ stores); (b) a functional network of Mg2+ transporters allowing for (1) the uptake of Mg2+ from the extracellular fluid, (2) its deposition and reposition within the intracellular compartments (which is essential for maintaining all the functions of Mg2+ in the cell), and (3) its extrusion from the cell into the extracellular fluid; and (c) a battery of regulatory components able to signal and to orchestrate the function of the network (see b) according to the demands of the cell. Given the importance of Mg2+ for the plethora of basal physiological processes in cells, probably all mammalian/human somatic cells and not only those intended for the absorption and transcellular transport of Mg2+ possess intracellular Mg2+ transport mechanisms allowing the deposition and reposition of Mg2+ within the cell and its organelles according to the actual needs of the cell (Nishizawa et al. 2007; Romani 2011). Among the npMgTs/Mg2+ homeostatic factors, not only the plasma membrane but also the mitochondrial (SLC41A3) and Golgi-localized (HIP14/HIP14L, MMgtT1, and MMgt2) npMgTs have been identified (Quamme 2010; Goytain and Quamme 2008; Goytain et al. 2008b). This is not surprising, as the mitochondria, endoplasmic reticulum (ER), and Golgi apparatus (GA) were long suspected of having functions including that of accumulating and storing Mg2+. The function of mitochondria in the storage of Mg2+ was experimentally established by Kubota and colleagues in PC12 cells, by Mastrototaro and colleagues in HEK-293 cells, and by Kolisek and colleagues in the mitochondria of yeasts (S. cerevisiae) (Kolisek et al. 2003; Kubota et al. 2005; Mastrototaro et al. 2015).

4.1

Mg2+ Transporters and/or Mg2+ Homeostatic Factors Localized to Mitochondria

In mammalian mitochondria, the concentrations of the matrix Mg2+ ([Mg2+]m) have been estimated to range between 0.2 and 1.5 mM (Kolisek et al. 2003; Jung et al. 1990; Rodríguez-Zavala and Moreno-Sánchez 1998). The [Mg2+]m measured in cardiac and liver mitochondria lie in range from 0.8 to 1.2 mM. Thus, [Mg2+]m has a same range to that of [Mg2+]i in the cytoplasm (Romani 2011; Rutter et al. 1990; Jung et al. 1990). Rudolf J. Schweyen’s group has demonstrated that the mitochondria of wild-type yeast (S. cerevisiae) are able to accumulate Mg2+ up to a final concentration of approximately 5 mM (Kolisek et al. 2003). At a transmembrane voltage (IMM) of
130 to
160 mV (Fig. 2) and an [Mg2+]e of 10 mM, the driving force for Mg2+ influx (ΔμMg) is extremely strong (
140 to
169 mV) and theoretically would result in an [Mg2+]m of 1,450 mM instead of the 5 mM observed in the yeast mitochondria under assay conditions as used by Kolisek and colleagues in their study (Kolisek et al. 2003; Rodríguez-Zavala and MorenoSánchez 1998; Iwatsuki et al. 2000). Therefore, Mg2+ self-evidently does not equilibrate freely across the IMM, suggesting the existence of a regulated Mg2+

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Fig. 2 The distribution of membrane potential across major intracellular compartments. ER endoplasmic reticulum, GA Golgi apparatus, IMM inner mitochondrial membrane, LYS lysosome

influx mechanism. Essentially similar conclusions have been drawn from the studies of Jung et al. (1990, 1997). As an alternative to a regulated Mg2+ influx mechanism, Kolisek and colleagues have proposed the existence of a Mg2+ efflux mechanism capable of balancing for Mg2+ influx (Kolisek et al. 2003). Kolisek and colleagues have identified Mrs2 (mitochondrial RNA splicing 2) to be a channel responsible for Mg2+ flux mediation into mitochondria (Figs. 1, 3, and 4) (Kolisek et al. 2003). Furthermore, they have demonstrated that the Mrs2mediated Mg2+ influx is entirely driven by the mitochondrial membrane potential (ΔψIMM) and inhibited by cobalt(III)hexaammine, an inhibitor of CorA (distant prokaryotic homolog of Mrs2) (Kolisek et al. 2003). These findings have been verified by the study of Schindl and coworkers who have shown by means of electrophysiology that Mrs2 fulfills all the prerequisites for a superconductive mitochondrial Mg2+ channel (Schindl et al. 2007). The depolarization of IMM (and thus a decrease of ΔψIMM) leads to the inevitable suspension of Mrs2 function (Kolisek et al. 2003). This is coherent with Mg2+ release in response to the depolarization of IMM (Kubota et al. 2005). Trapani and Wolf have quoted, in their review, the work of Kubota and colleagues stating that Mrs2-mediated Mg2+ efflux might take place in mitochondria upon the depolarization of IMM (Kubota et al. 2005; Trapani and Wolf 2015). Considering the enormous Δψ on IMM, a very

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Fig. 3 Recycling of Mg2+, Na+, and Ca2+ on inner mitochondrial membrane. MCU mitochondrial Ca2+ uniporter, NCE Na+/Ca2+ exchanger, NHE Na+/H+ exchanger, NME Na+/Mg2+ exchanger, Mrs2 mitochondrial Mg2+ channel

strong ΔμMg and an almost negligible Δ[Mg2+] between the intermembrane space [Mg2+]is and the matrix [Mg2+]m, scenario in which Mrs2 act as a Mg2+-efflux mechanism is almost impossible, even during an event of drastic depolarization (Kolisek et al. 2003; Vergun et al. 2003; Corkey et al. 1986). Furthermore, the overall structure of the Mrs2 channel, the organization of the selective filter, and the complex gating mechanism are not in support of the hypothesis that the channel may conduct Mg2+ efflux under certain conditions (Sponder et al. 2013a; Khan et al. 2013). The functionally inactive, mutant Mrs2 causes in dmy/dmy rats a mitochondrial disease hallmarked by the demyelination of the neurons (Kuramoto et al. 2011; Kuwamura et al. 2011). The proton (H+) gradient across the IMM generates the major motive force powering the transport of a plethora of solutes across this membrane. Thus, the mitochondrial Mg2+ efflux system was assumed to be directly or indirectly coupled to H+ influx. The experimental work of Rutter and colleagues using rat heart mitochondria supports the existence of a mitochondrial H+/Mg2+ exchanger (Fig. 4) (Rutter et al. 1990). Furthermore, long-chain fatty acids induce the rapid release of Mg2+ from rat liver mitochondria in alkaline media, presumably via a Mg2+/Me+ or an H+/Mg2+ exchanger (Schönfeld et al. 2002). However, until

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Fig. 4 The mitochondrial (IMM) Mg2+ transport circuit (Mrs2, SLC41A3, APC, and HME). APC ATP-Mg/Pi carrier, HME H+/Mg2+ exchanger (?, mechanism encoded by yet unknown molecular entity), IMM inner mitochondrial membrane, Mrs2 Mg2+ channel, NME Na+/Mg2+ exchanger

now the molecular identity of the mitochondrial transporter capable of Mg2+ efflux via a mechanism of H+/Mg2+ exchange remains elusive. Recently, the group of Sponder has provided experimental evidence that npMgT SLC41A3 is a Na+-coupled Mg2+ efflux system (very likely a Na+/Mg2+ exchanger) that resides in the IMM (Figs. 1, 3, and 4) (Mastrototaro et al. 2016). This finding is also supported by the observation that the 25Mg2+ uptake in wild type (SLC41A3+/+) and SLC41A3
/
mice is alike (de Baaij et al. 2016). The exact nature of the Na+-Mg2+ transport coupling via SLC41A3 and the stoichiometry of this process remains to be addressed. Perhaps, the further characterization of SLC4A3 will shed more light on the observation of Zhang and Melwin that the elevation of [Na+]i induces an efflux of Mg2+ from intracellular pool(s) (mitochondria) in rat sublingual mucous acini (Zhang and Melvin 1996). Moreover, an increase of the classic cytosolic secondary messenger cAMP has been reported to activate the release of Mg2+ from mitochondria (Romani et al. 1991). cAMP is an important cofactor/activator of PKA. Whether PKA plays a role in the activation of SLC41A3 remains to be examined. However, the cAMPdependent activation of PKA followed by the phosphorylation of the plasma membrane Na+/Mg2+ exchanger SLC41A1 has clearly been demonstrated as being an essential step toward the release of Mg2+ from the cell (Mastrototaro et al. 2015;

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Kolisek et al. 2013a; Sponder et al. 2017). Therefore, keeping in mind the shared ancestry of SLC41A1 and SLC41A3, it would be unsurprising if SLC41A3 also undergoes PKA-mediated activation (Fig. 5). Recently, this hypothesis has become even more feasible because of the discovery of A-kinase-anchoring proteins (AKAP), namely, AKAP121 and SPHKAP/SKIP (sphingosine kinase type-1 anchor/interacting protein), which are known to tether PKA to the outer mitochondrial membrane (OMM) and intermembrane space within the proximity of its local targets (Fig. 5) (Feliciello et al. 2005; Kovanich et al. 2010; Means et al. 2011; Lefkimmiatis et al. 2013). The existence of an independent intramitochondrial cAMP signaling circuit consisting of the bicarbonate-activated soluble adenylyl cyclase (sAC), PKA holoenzyme, and phosphodiesterase 2a (PDE2A) has also been reported (Lefkimmiatis et al. 2013; Wuttke et al. 2001; Zippin et al. 2003; Sardanelli et al. 2006; Acin-Perez et al. 2009, 2011a, b). Hence, strictly hypothetically, even a matrix-based cAMPPKA regulation of SLC41A3-mediated Mg2+ would be possible (Fig. 5).

Fig. 5 Strictly hypothetical model of SLC41A3 regulation via cAMP-PKA and Akt/PKB signaling pathways in mitochondria. AC adenylyl cyclase, Akt/PKB protein kinase B, AKAP1 A-kinaseanchoring protein 1, APC ATP-Mg/Pi carrier, CM cytoplasmic membrane, G glucagon, GP G protein, HME H+/Mg2+ exchanger (?, mechanism encoded by yet unknown molecular entity), IMM inner mitochondrial membrane, INS insulin, Mrs2 mitochondrial Mg2+ channel, NME Na+/Mg2+ exchanger, OMM outer mitochondrial membrane, PDE2a phosphodiesterase 2a, PKA protein kinase A, RTK receptor tyrosine kinase, sAC soluble adenylyl cyclase, SKIP sphingosine kinase type 1 interacting protein

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Insulin (INS) decreases the concentration of the cytosolic cAMP via the classic INS-signaling cascade IR-PI3K-Akt/PKB by the activation of phosphodiesterase 3b (PDE3b) and consequently limits the activation of the cytosolic PKA (Mastrototaro et al. 2015). INS promotes the efflux of Mg2+ from mitochondria (and perhaps also other intracellular Mg2+ stores) via a cAMP-PKA-independent mechanism concomitant with the translocation of PKB into mitochondria (Fig. 5) (Mastrototaro et al. 2015; Bijur and Jope 2003). The exact nature of the INS action on the process of mitochondrial Mg2+ release and its correlation with the translocation/accumulation of Akt/PKB into mitochondria remain elusive. Without doubt, PKA and Akt/PKB play fundamental roles in the regulation of cytosolic and mitochondrial [Mg2+] and the regulation of mitochondrial homeostasis per se. Furthermore, both of these kinases significantly influence cellular energetics and metabolic activity. Thus, further research aimed at explaining the role of PKA and Akt/PKB in the regulation of the mitochondrial accumulation of Mg2+ and its release from mitochondria is urgently needed (Zhang et al. 2017a; Manning and Toker 2017). Recently, van Ooijen and colleagues have explained a possible molecular background behind the involvement of [Mg2+]i and its oscillations in the regulation of the circadian clock in eukaryotes (Feeney et al. 2016). Interestingly, PKA and Akt/PKB have both been substantially implicated in the regulation of the circadian clock (Huang et al. 2007; Noguchi et al. 2018; Luciano et al. 2018). Thus, we can assume that except for SLC41A1, also the components of mitochondrial Mg2+ homeostasis (Mrs2, SLC41A3 and APC) and their regulatory network (very likely PKA and Akt/PKB) form an intricate biological mechanism making mitochondria not only “a battery” but also “a tuning mechanism” for the circadian clock. Further research into the intersection between mitochondrial homeostasis and cellular/mitochondrial Mg2+ homeostasis is undoubtedly of great importance, especially for the field of chronomedicine and for research into degenerative diseases, in which CHRONO-component plays an important role. ATP-Mg/Pi carrier (APC; or short Ca2+-binding mitochondrial carrier, SCaMC; or solute carrier family 25 member A24, A25, A23, A41 (SLC25A24, SLC25A25, SLC25A23, SLC25A41)), which is localized in the IMM, facilitates an electroneutral reversible exchange between MgATP2
and HPO42
(Figs. 1 and 4) (Run et al. 2015; Traba et al. 2009; Joyal and Aprille 1992). APC remains inactive unless stimulated by a cytosolic Ca2+ signal (Nosek et al. 1990). While under physiological conditions, the preferred substrates for the APC are MgATP2
and Pi (HPO42
), but in the absence of Mg2+, ADP (HADP2
) can also be transported via the APC (Joyal and Aprille 1992; Tewari et al. 2012). Nevertheless, this transporter does not transport ionized Mg2+ alone; complexed with ATP, its impact on the modulation of mitochondrial or cytosolic [Mg2+] might be significant (Tewari et al. 2012; Kun 1976). However, no information has been acquired about any possible crosstalk between APC and other mitochondrial Mg2+ transporters. The ADP/ATP carrier (AAC, or solute carrier family 25 member A4, A5, A6 (SLC25A4–6)) is the major carrier that exports ATP out of the matrix for energy consumption while importing ADP for the production of new ATP by the ATP

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synthase, and its functional defects can be detrimental for the cell (Run et al. 2015; Fiore et al. 1998; Klingenberg 2008). Whereas AAC accounts for the bulk of ADP/ATP recycling in the matrix, APC is important for mitochondrial activities in the matrix that depend on adenine nucleotides, such as gluconeogenesis and mitochondrial biogenesis (Run et al. 2015). Quoting Romani, Trapani, and Wolf have stated that, although the AAC substrate of choice is ATP, it might change to MgATP in some cases, e.g., following cAMP or thyroid hormone stimulation (Romani 2011; Trapani and Wolf 2015). However, this statement is contradicted by several works concluding that MgATP or MgADP is not transported through AAC (Run et al. 2015; Pfaff et al. 1969; Nury et al. 2006). Therefore, currently, questions remain as to whether AAC, alone or in the mitochondrial permeability transition pore complex, contributes to Mg2+ transport across IMM (Karch and Molkentin 2014). Pharmacological experiments with SNAP, 8-Br-cGMP, diazoxide, and several inhibitors, performed by Yamanaka and colleagues, have revealed that the NO – cGMP – protein kinase G (PKG) signaling pathway triggers an increase in [Mg2+]i and that Mg2+ mobilization is attributable to the Mg2+ release from mitochondria induced by mitoKATP channel opening (Yamanaka et al. 2013). Furthermore, Mg2+ release is potentiated by the positive feedback loop including mitoKATP channel opening, mitochondrial depolarization, and PKC activation (Yamanaka et al. 2013). Despite the ongoing debate about the physical existence of the mitoKATP channel, the recreation of the experiments of Yamanaka and colleagues in rodent or humanderived cells/cell lines with silenced expression or overexpression of mitochondrial Mg2+ extruder SLC41A3 would be of interest (Yamanaka et al. 2013; Garlid and Halestrap 2012). Yeast (S. cerevisiae) Lpe10 (or MFM1; Mrs2 function modulating factor 1) belongs to the CorA superfamily of Mg2+ transporters. Moreover, it is homologous to yeast Mrs2 (approximately 32% sequence homology and presence of the G-M-N Mg2+ binding motive) (Gregan et al. 2001b). Sponder and colleagues have utilized an intriguing set of complementation experiments in order to demonstrate that both Lpe10 and Mrs2 are functionally related and that they form complexes together but cannot substitute for each other (Sponder et al. 2010a). Deletion of Lpe10 leads to a rapid loss of the membrane potential on IMM, a phenomenon otherwise not seen when only Mrs2 is deleted (Sponder et al. 2010a). Lpe10 alone is not able to mediate the high-capacity Mg2+ influx otherwise seen with Mrs2. When coexpressed with Mrs2, they yield a unique reduced Mg2+ conductance in comparison with that of Mrs2 channels (Sponder et al. 2010a). A homolog of Lpe10 is not found in mammalian/human mitochondria. However, we cannot exclude that, during the evolution, the Mrs2-modulating role of Lpe10 was overtaken by an as yet unknown mitochondrial protein innate to mammalian/human mitochondria. Only further targeted research may address this issue. Recently, a mitochondrial Mg2+ efflux system constituted by Mme1 (mitochondrial Mg2+ exporter 1) protein has been described in S. cerevisiae, followed by the discovery of its ortholog, dMme1 protein, in Drosophila melanogaster (Cui et al. 2015, 2016). No human ortholog of Mme1 or dMme1, if any, has yet been identified. An alteration in the expression of dMme1, although only resulting in a change of

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about 10% in mitochondrial Mg2+ levels in either direction, leads to a significant survival reduction in Drosophila (Cui et al. 2016). Despite the excitement brought about by the discovery of Mme1 and dMme1, further experiments confirming its role in the mitochondrial Mg2+ homeostasis of single-cellular and lower multicellular eukaryotes are necessary. In particular, the mode of operation of both orthologs should be explained. Testing its ability to functionally complement for the deletion of SLC41A3 would also be of interest.

4.2

Mg2+ Transporters and/or Mg2+ Homeostatic Factors Localized to Endoplasmic Reticulum

The high metabolic activity and the large estimated ΔψER of
75 to
95 mV across the membrane of ER make this cellular compartment, similar to mitochondria, not only “a Mg2+ consumer” but also a suitable compartment for storing Mg2+ (with a total Mg concentration estimated as being between 14 and 18 mM) (Fig. 2) (Romani 2011; Qin et al. 2011). Unfortunately, among npMgTs characterized by Goytain and Quamme’s group, no candidates have been predicted to localize to ER compartment (Quamme 2010). In the regnum of plants, Li and colleagues have mapped the Mg2+ transporter AtMGT4 (Arabidopsis thaliana Mg2+ Transporter 4), a distant homolog of yeast Mrs2 and a member of the CorA superfamily, to ER (Li et al. 2015). There is no reason to suggest that the ER of animal cells differ from the ER of plant cells with respect to the existence of ER-localized Mg2+ transporters/Mg2+ homeostatic factors. Presently, many indirect indices argue for the existence of an ER-localized Mg2+ transporter in mammalian/human cellular systems; however, only future experimental attempts will uncover their identities. ATP13A4, a member of the subfamily of P5-type ATPases, is thought to act as a cation transporter and can serve as an example of a promising candidate (Schultheis et al. 2004). Subcellularly, it localizes to the ER when expressed in COS-7 cells (Fig. 1) (Vallipuram et al. 2010). Will and colleagues have hypothesized that ATP13A4 transports Mg2+ (Will et al. 2010). However, the same authors stress that the substrate specificity of ATP13A4 is as yet only poorly understood.

4.3

Mg2+ Transporters and/or Mg2+ Homeostatic Factors Localized to the Golgi Apparatus

In contrast to ER, a screen performed by Goytain and Quamme’s group has revealed the identities of four genes encoding for proteins putatively localized to the GA and post-Golgi vesicles, namely, MMgT1, MMgT2 (not found in the human genome but present in mouse), and HIP14 and HIP14L (Quamme 2010; Goytain and Quamme 2008; Goytain et al. 2008b).

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Murine MMgT1 (membrane Mg2+ transporter 1) and MMgT2 (membrane Mg2+ transporter 2) are proteins putatively localized in the GA and post-Golgi vesicles and possess two transmembrane helices but show no structural similarities to other known Mg2+ transporters (Fig. 1) (Quamme 2010; Goytain and Quamme 2008). Murine MMgT1 and MMgT2 are 97 and 81% similar to human MMgT1 (Quamme 2010; Goytain and Quamme 2008). When expressed in X. laevis oocytes, they conduct the electrogenic transport of Mg2+ as determined with TEV analysis and fluorescence measurements (apart from other cations, Table 2) (Quamme 2010; Goytain and Quamme 2008). The observed Mg2+ transport was saturable with a Km ¼ 1.47  0.17 mM (MMgT1) or 0.58  0.07 mM (MMgT2) (Quamme 2010; Goytain and Quamme 2008). As it is generally assumed that proteins with two membrane-spanning helices are unable to support the transport of any ion/solute, Goytain and Quamme have concluded that MMgT1 and MMgT2 form homooligomeric or heterooligomeric complexes to sustain their transport function (Quamme 2010; Goytain and Quamme 2008). The ability to transport Mg2+ by MMgT1 and/or MMgT2 has not yet been demonstrated in a homologous (mammalian) expression system. Furthermore, the previously discussed concerns regarding the use of TEV for the establishment of the ion permeation profile should be considered before any data is used for the design of future studies. The localization data of both putative Mg2+ transporters are based only on confocal microscopy (Goytain and Quamme 2008). To show bona fide the cellular localization of MMgT1 and MMgT2, a complementary experimental approach leading to the purification of GA (e.g., differential and density gradient centrifugation) and the immunodetection of both proteins in the purified GA fraction should be utilized. HIP14 (huntingtin-interacting protein 14) and HIP14L (HIP14-like protein, 64% homologous to HIP14) have been proposed to reside in the membrane of GA (HIP14 is predicted to contain five or six transmembrane helices and HIP14L seven transmembrane helices) enabling the electrogenic transport of Mg2+ (Fig. 1) (Quamme 2010; Goytain et al. 2008b; Ducker et al. 2004). This conclusion has been made based on the data from TEV experiments performed on X. laevis oocytes expressing murine HIP14 or HIP14L (Quamme 2010; Goytain et al. 2008b). The ion selectivity of HIP14 and HIP14L is quite broad (Table 2); however, showing a clear preference for Mg2+ and Sr2+ (Quamme 2010; Goytain et al. 2008b). The Mg2+ transport recorded by Goytain and colleagues is saturable with Km ¼ 0.87  0.02 mM (HIP14) or 0.74  0.07 mM (HIP14L) (Quamme 2010; Goytain et al. 2008b). HIP14 has been characterized as palmitoyl acyltransferase essential for the trafficking and functioning of huntingtin with substantial involvement in the ethiopathology of Huntington disease (Ducker et al. 2004; Yanai et al. 2006; Butland et al. 2014). Considering the latter and their own data, Goytain and colleagues have concluded that HIP14 and HIP14L fulfill the requirements for being chanzymes (natural fusion protein consistent of ion channel and enzyme) (Quamme 2010; Goytain et al. 2008b). Unfortunately, although no doubt exists about HIP14/HIP14L functioning as a palmitoyl acyltransferase, clear evidence is lacking that it operates as a Mg2+ transporter in GA of mammalian/human cells.

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Schapiro and Grinstein have assumed that ΔψGA of GA membrane is small almost close to 0 mV (Fig. 2) (Schapiro and Grinstein 2000). ΔψGA around 0 mV and the presumable lack of an inwardly oriented Mg2+ concentration gradient between the cytosol and the lumen of GA would clearly not be in favor of GA-localized Mg2+ channels/chanzymes as predicted by Goytain and colleagues (Schapiro and Grinstein 2000; Günther 2006a). Instead, the existence of GA-localized Mg2+ transport mechanism(s) powered by ATP (Mg2+ pump) or a secondary motive force (H+, Na+) would be more sensible.

4.4

Mg2+ Transporters and/or Mg2+ Homeostatic Factors Localized to Lysosomes

The lysosomal membrane potential ΔψLYS was determined to be, on average, +19 mV (positive on the luminal side, Fig. 2) (Koivusalo et al. 2011). Therefore, on the presumption of the equimolar distribution of Mg2+ between the cytosolic and lysosomal compartments, any transport of positively charged Mg2+ into lysosomes can be supported only via primary or secondary active Mg2+ transport mechanisms. The Caenorhabditis elegans ortholog of human P-type ATPase (subfamily P5B) ATP13A2 (PARK9), CATP-6, is speculated to function as a lysosomal Mg2+ transporter (Lambie et al. 2013). Whether human ATP13A2 functions as a Mg2+ transporter/lysosomal Mg2+-mediating pump remains to be further researched and convincingly demonstrated (Fig. 1).

4.5

Mg2+ Transport Across Nuclear Membrane

In their most recent work, Maeshima and colleagues have concluded that Mg2+ released from the MgATP complex after its hydrolysis contributes to mitotic chromosome condensation with increased rigidity, suggesting a novel regulatory mechanism for higher-order chromatin organization by the intracellular MgATP complex balance (Maeshima et al. 2018). Because of DNA and RNA metabolism, which is known to be Mg2+-dependent, Mg2+ is of high demand by the nucleus (Nishizawa et al. 2007). The major nuclear Mg2+ influx/efflux mechanism is believed to be constituted by the nuclear pore that allows Mg2+ to move freely across the porous nuclear membranes simply by diffusion (Romani 2011).

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Putative and Confirmed Mg2+ Transporters/Mg2+ Homeostatic Factors with Unclear Localization SLC41A2 (Solute Carrier Family 41 Member A2)

Member A2 of the solute carriers family 41 (SLC41A2), which like other members of this family is distantly homologous to the bacterial Mg2+ transporter MgtE, was predicted by Sahni and colleagues to reside in cytoplasmic membrane, as based on results from experimental evidence (Sahni et al. 2007). The protein comprises 11 transmembrane helices with an “N-terminus outside and C-terminus inside” orientation of its termini (Sahni et al. 2007). Since the orientation of SLC41A2 appears to be the opposite of that predicted by the structure of prokaryotic MgtE proteins or SLC41A1, the same group has subsequently speculated that the observed plasma membrane localization of SLC41A2 reflects aberrant cell surface targeting attributable to the overexpression of the protein (Sahni et al. 2007; Sahni and Scharenberg 2013). Despite the targeting and placement of SLC41A2 to the cytoplasmic membrane having not been completely rejected, the hypothesis that SLC41A2 plays its roles in intracellular membranous compartments and vesicles is currently better accepted (Sahni et al. 2007; Sahni and Scharenberg 2013). Similar to other npMgTs functionally characterized by the group of Goytain and Quamme, SLC41A2, when overexpressed in X. laevis oocytes, also conducts the electrogenic transport of Mg2+ and of other cations (Table 2) (Quamme 2010; Goytain and Quamme 2005b). Sahni and colleagues have attempted to identify Mg2+-specific currents in DT40 cells overexpressing human SLC41A2 with patch clamp; however, these attempts remain unsuccessful (Sahni et al. 2007). Although the data on the mode of Mg2+ transport via SLC41A2 are puzzling, we can safely say that, with high probability, SLC41A2 is a Mg2+ transporter. This assumption is underpinned by the ability of SLC41A2 to complement the growth/ proliferation defect of DT40 TRPM7-KO cells, when they are cultured at physiological [Mg2+]e. TRPM7-deficient DT40 cells induced to express SLC41A2 proliferate more slowly than wild-type DT40 cells in culture medium containing physiological levels of Mg2+, but in contrast to the TRPM7-deficient cells, they are able to proliferate continuously (Sahni et al. 2007). Furthermore, Sahni and colleagues have determined the Mg2+ uptake (measured by the ratio of 26Mg2+/ 24 Mg2+) to be approximately twofold to threefold higher in SLC41A2overexpressing cells as compared with the cells without induced expression of transgenic SLC41A2 and even greater than that observed in the wild-type DT40 cells (Sahni et al. 2007). The last mentioned results provide direct evidence that SLC41A2 overexpression correlates with enhanced Mg2+ accumulation. Whether the gene SLC41A2 is truly magnesiotropic remains controversial. Goytain and Quamme have used real-time RT-PCR analysis of MDCT cells cultured in medium with [Mg2+]e of 1 mM or in Mg2+ free medium for 16 h and found no change in SLC41A2 expression; the same result was found to be the case with kidney cortical tissue harvested from mice fed with a normal or low Mg2+ diet for 5 days

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(Goytain and Quamme 2005b). In a review on “the modern Mg2+ transporters,” Quamme has however postulated that “SLC41A1–3 transcripts are present in many tissues of normal mice. Furthermore, the mRNAs in these tissues are increased with low Mg2+” (Quamme 2010). Despite rather strong experimental evidence, especially from the laboratory of Sahni and colleagues, SLC41A2 is an only marginally researched Mg2+ transporter, which certainly deserves much more attention, as it could be a key player in the cellular Mg2+ homeostasis, like members A1 and A3 from the same family of solute transporters.

4.6.2

The CNNM (Cyclin and CBS Domain Divalent Metal Cation Transport Mediator) Family, “Enfant terrible” Among Mg2+ Transporters/Mg2+ Homeostatic Factors

The CNNM family consists of four members (CNNM1–CNNM4) that were formerly known as ancient conserved domain proteins (ACDP). Their original name was based on the observation that these genes/proteins possessed a highly conserved domain also found in other species from bacteria to mammals. The most conserved regions of CNNMs are the two cystathionine beta-synthase (CBS) domains and the DUF21 domain that are both also found in bacterial CorC (Wang et al. 2003). The high homology of ACD proteins to the bacterial CorC protein which is involved in Mg2+ and Co2+ efflux early led to the speculation that these proteins are involved in ion transport (Gibson et al. 1991; Wang et al. 2004). Although sequence conservation among the family members is remarkably high (for the human and mouse family members: 55.3% of amino acid identity and 83.3% of amino acid homology in the conserved region), their expression pattern, localization within the cell (Fig. 1), and their function appear to be divergent and are still a matter of debate (Wang et al. 2004).

CNNM2 (Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 2) CNNM2 is the best studied representative of this family and, at the same time, is the most controversial. Wang and colleagues have demonstrated the expression of CNNM2 in most mouse tissues; however, the expression levels are generally low, except in the brain, kidney, and liver (Wang et al. 2003). This finding has subsequently been confirmed in mice by Goytain and Quamme who have found the highest expression in kidney and brain (Goytain and Quamme 2005d). Abundant amounts have also been detected in the heart and liver, with lower expression in the small intestine and colon. As mentioned previously, the expression of CNNM2 is influenced by the food Mg content and displays increased expression in the kidneys of mice fed with a low Mg diet and in cultured MDCT cells cultured in low Mg medium (Goytain and Quamme 2005d). Mouse CNNM2, when expressed in

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Xenopus oocytes, exhibits currents for Mg2+ and other divalent cations (Table 2) and therefore behaves as a rather unspecific cation transporter. However, as the Km was within a physiological range only for Mg2+, Goytain and Quamme concluded that CNNM2 primarily acts as a Mg2+ transporter (Quamme 2010; Goytain and Quamme 2005d). The assumption that CNNM2 acts as a Mg2+ transporter seems to be supported by a study of Sponder and colleagues who have demonstrated that the longest splice variant of human CNNM2 (875 amino acids) partially complements the Mg-dependent growth defect of Salmonella strains MM281 (deficient for MgtA, MgtB, and CorA). Only the somewhat shorter splice variant 2 fails to do so (Sponder et al. 2010b). Further evidence for the involvement of CNNM2 in Mg2+ transport has come from a study that has identified a connection between CNNM2 and dominant hypomagnesemia. This rare disorder is characterized by severely lowered serum Mg2+ levels most probably caused by defective tubular reabsorption. Such a notion is also supported by the localization of CNNM2 on the basolateral membrane of DCT cells and its strong expression in the kidney (Stuiver et al. 2011; de Baaij et al. 2012). Interestingly, the electrophysiological characterization of CNNM2 in HEK293 cells yields Mg2+-sensitive Na+ currents and thereby divergent results from those observed in Xenopus oocytes. The authors have consequently concluded that CNNM2 is a regulatory factor rather than a direct mediator of Mg2+ transport (Stuiver et al. 2011). Currents for Na+ have also been reported by another group when CNNM2 is overexpressed in HEK293 cells (Yamazaki et al. 2013). Arjona and colleagues have used zebrafish as a model system to study the function of CNNM2 and have reported disturbed brain development and reduced body Mg content as consequences of the deletion of the gene. They have furthermore demonstrated, with the aid of stable isotope 25Mg2+, that the overexpression of mouse CNNM2 in HEK293 cells increases the cellular Mg content. However, since this effect is abolished by the TRPM7 inhibitor 2 APB, the authors have concluded that this effect is indirect and presumably mediated by a regulatory effect of CNNM2 on the Mg2+ permeable channel TRPM7 (Arjona et al. 2014). This is in contrast to the data obtained by Hirata and colleagues with the Mg2+ indicator Magnesium Green, which has shown the strong and remarkably fast efflux of Mg2+ within seconds when CNNM2 is expressed in HEK293 cells. They have further found the CBS domains that directly bind ATP in a Mg2+-dependent manner as being indispensable for Mg2+ efflux (Hirata et al. 2014). The same group of Miki has subsequently used mice to investigate the function of CNNM2 in an animal model. Homozygous knockout mice have an embryonic lethal phenotype; heterozygous mice are viable and exhibit impaired Mg reabsorption with reduced serum Mg levels. The same phenotype is observed in mice with a kidneyspecific deletion of CNNM2 (Funato et al. 2017). In contrast to these functional data from mice, Sponder and colleagues have employed mag-fura-2, Mg2+-sensitive fluorescent dye, in an in vitro model to investigate the Mg2+ transport activity of two of the three known splice variants of human CNNM2 under conditions favoring both Mg2+ influx and efflux. Although

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the same expression system, HEK293 cells as in previous studies, were used neither electroneutral nor was electrogenic Mg2+ transport detected for the two splice variants in the overexpressing cells. The authors have concluded that CNNM2 acts as Mg2+ homeostatic factor without being a Mg2+ transporter itself (Sponder et al. 2016). Recently, a role of CNNM2 in tumorigenesis has been proposed. The protein interacts with PRL-1, a member of the so-called phosphatases of regenerating liver; these phosphatases exhibit high expression in most solid tumors and hematological cancers and are considered to be highly oncogenic. Binding between the two proteins is mediated via the interaction of an amino acid in the CBS domain of CNNM2 and the catalytic domain of the phosphatase. The authors speculate that this interaction increases the cellular magnesium content, thereby aggravating tumor progression and metastasis formation (Giménez-Mascarell et al. 2017). In summary, great efforts have been undertaken to elucidate the molecular function of CNNM2. In view of the connection between mutations in CNNM2 and patients suffering from hypomagnesemia and knockdown experiments in mouse and zebrafish, the involvement of CNNMs in cellular Mg2+ homeostasis is unequivocal. However, the strongly divergent behavior of CNNM2 in various expression systems and experimental setups complicates rather than clarifies the situation and has led to much conflicting and contradictory data. A clear conclusion cannot therefore be drawn about the function of this protein in cellular Mg2+ homeostasis.

CNNM4 (Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4) CNNM4 has a relatively broad expression pattern with its highest expression in intestinal epithelia (Wang et al. 2003; de Baaij et al. 2012). The first indication for a function in metal ion homeostasis came from the observation that the expression of the protein in HEK293 cells resulted in an increased sensitivity to copper, manganese, and cobalt. The toxicity of these metal ions was aggravated by the coexpression of CNNM4 together with COX11 suggesting a possible functional dependence of CNNM4 on other proteins (Guo et al. 2005). Mutations in CNNM4 do not influence blood Mg concentrations and cause Jalili syndrome in humans, a combination of recessively inherited cone-rod dystrophy and amelogenesis imperfecta. Given the broad expression pattern, the findings that only the retina and ameloblasts are affected by the expression of mutant variants of CNNM4 and that therefore phenotypic consequences are restricted to retinal function and tooth biomineralization are of interest (Parry et al. 2009). CNNM4 has also appeared together with CNNM2 and CNNM3 in a genomewide association study on common single nucleotide polymorphisms SNPs being associated with serum magnesium concentrations (Meyer et al. 2010). Direct evidence for an involvement of CNNM4 in Mg2+ homeostasis has come from Miki’s group who have characterized CNNM4 in mice. Expression of the

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protein has been found to be high in the intestine where it localizes to the basolateral membrane. No expression in the kidney has been detected. CNNM4 knockout mice are viable with no obvious phenotype. However, the animals exhibit lower serum Mg concentration, a result that has been attributed to impaired intestinal Mg2+ absorption. The transport function was directly assessed by the use of the Mg2+ indicator Magnesium Green. When CNNM4 was expressed in HEK293 cells, the protein mediated a very rapid efflux of Mg2+ that was dependent on extracellular Na+. Similar to CNNM2, the CBS domains are also essential for the transport activity of CNNM4 (Hirata et al. 2014). From their data, the authors conclude that CNNM4 forms a high capacity Mg2+ efflux system that is localized in the basolateral membrane of the intestine and that acts as a counterpart to the TRPM6/7 channelmediated Mg2+ uptake system on the apical side. Of note is the observation that the knockout of CNNM4 in mice results in amelogenesis imperfecta. However, in contrast to descriptions of Jalili syndrome in humans, the retina remains unaffected (Yamazaki et al. 2013).

CNNM1 and CNNM3 (Cyclin and CBS Domain Divalent Metal Cation Transport Mediator3 and 4) Knowledge about the two other members of this family, namely, CNNM1 and CNNM3, is still scarce. Wang et al. have reported the high expression of CNNM1 in the brain, whereas only low levels have been detected in the kidney, testis, and most other tested tissues. For CNNM3, the highest expression has been observed in the brain, kidney, liver, and heart and very low levels in skeletal muscles (Wang et al. 2003). Together with CNNM2 and CNNM4, CNNM3 has been also found in the aforementioned genome-wide association study as being linked to the serum magnesium concentration (Meyer et al. 2010). Studies directly investigating the possible transport activity of the two proteins are rare. In a study on the pufferfish Takifugu obscurus, CNNM3 was upregulated in the kidney when the animals were kept in salt water. Immunohistochemical investigations revealed expression in the proximal tubule where CNNM3 was localized to the lateral membrane. The expression of CNNM3 in Xenopus oocytes resulted in a significant decrease of the cellular Mg2+ concentration (Islam et al. 2014). The only study in a mammalian model system was performed in the laboratory of Miki. They investigated the importance of the CBS domains for all four members of the CNNM family. CNNMs were expressed in HEK293 cells, and Magnesium Green was used for intracellular Mg2+ detection. In contrast to the aforementioned strong activity of CNNM2 and CNNM4, only a weak efflux was detected for CNNM1, and no activity in cells expressing CNNM3 was observed in this experimental setup (Hirata et al. 2014). Interestingly, for CNNM3 an interaction with two members of the aforementioned phosphatases of regenerating liver (PRLs), namely, PRL-2 and PRL-3, has also been reported suggesting a role of CNNM3 in tumor development and progression (Zhang et al. 2017b).

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Putative and Confirmed Mg2+ Transporters/Mg2+ Homeostatic Factors with Plasma Membrane Localization

Several Mg2+ influx and/or efflux mechanisms have been foreseen to exist in the cytoplasmic membrane (Nishizawa et al. 2007; Romani 2011; Schweigel et al. 2000). Presently, only chanzymes TRPM6/7 and Na+/Mg2+ exchanger SLC41A1 are well characterized at the molecular level (Schweigel-Röntgen and Kolisek 2014; Penner and Fleig 2007; Sponder et al. 2017; Cabezas-Bratesco et al. 2015). It is universally accepted that both chanzymes represent a channel component responsible for the transport of the majority of extracellular Mg2+ into the cell. In vitro, also SLC41A1 has been shown to mediate Mg2+ uptake under conditions strongly supporting Mg2+ influx. However, it has to be stressed out that these conditions were far from physiological to most of the tested cell types (SchweigelRöntgen and Kolisek 2014; Kolisek et al. 2008, 2012; Fleig et al. 2013). Whether SLC41A1 mediates Mg2+ influx also in vivo under physiological conditions is unclear and a subject of ongoing debates. Unequivocally, confirmed by several independent and unbiased studies, SLC41A1 was shown to be an ubiquitously expressed (Table 3), major cellular Mg2+ efflux system functionally conserved from fish to Man (Schweigel-Röntgen and Kolisek 2014; Kolisek et al. 2008, 2012; Fleig et al. 2013; Islam et al. 2013; Hurd et al. 2013; Lin et al. 2014). Thus, it could be stated with confidence that TRPM6/7 chanzymes together with Mg2+ efflux-mediating carrier SLC41A1 constitute the Mg2+ transport circuit of cytoplasmic membrane (Fig. 6).

4.7.1

SLC41A1 (Solute Carrier Family 41 Member A1)

SLC41A1 is a plasma membrane-localized protein (Fig. 1) possessing 10 or 11 transmembrane helices with either both termini oriented intracellularly (10 transmembrane helices model) or with the N-terminus oriented toward the inside and an extracellular C-terminus (11 transmembrane helix model) (Kolisek et al. 2008; Sponder et al. 2013b; Mandt et al. 2011). The putative role of SLC41A1 in cellular Mg2+ homeostasis, more precisely in Mg2+ transport, was assumed by Wabakken and colleagues based on its distant homology to the bacterial MgtE family of Mg2+ transporters (Wabakken et al. 2003). Shortly after, it was recognized by Goytain and Quamme as being an MgG, and by using TEV, mouse SLC41A1 has been shown to mediate electrogenic Mg2+ influx (but also influx of other cations; Table 2) when overexpressed by X. laevis oocytes (Quamme 2010; Goytain and Quamme 2005a). Kolisek and colleagues have utilized the patch clamp technique attempting to identify SLC41A1-specific Mg2+ currents in HEK293 cells overexpressing human SLC41A1. However, these attempts remained unsuccessful. Instead of identifying a SLC41A1-connected Mg2+ conductance, the currents induced by SLC41A1

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Fig. 6 Current model of the Mg2+ transport circuit on cytoplasmic membrane (CM). It consists of a Mg2+ ion channel allowing for Mg2+ influx (chanzymes TRPM6/7) and a Na+/Mg2+ exchanger (NME; SLC41A1) mediating Mg2+ efflux

overexpression have been identified as endogenous Cl
currents, recruited by depletion of intracellular Mg2+ and blockable by the broad-spectrum Cl
transport antagonist DIDS (Kolisek et al. 2008). Nevertheless, in a strain of Salmonella enterica MM281 exhibiting disruption of all three distinct magnesium transport systems (CorA, MgtA, and MgtB), overexpression of human SLC41A1 functionally substituted for these transporters and restored the growth of the mutant bacteria at [Mg2+] otherwise nonpermissive for growth (Kolisek et al. 2008). Mandt and colleagues have also performed functional complementation experiments showing the ability of SLC41A1 to functionally substitute for TRPM7 in TRPM7-KO DT40 cells with heterologous expression of wild-type SLC41A1 (Mandt et al. 2011). Furthermore, Kolisek and colleagues have shown that overexpression of SLC41A1 provided HEK293 cells with an increased Mg2+ efflux capacity. With outwardly directed Mg2+ gradients, a SLC41A1-dependent reduction of the [Mg2+]i accompanied by a significant net decrease of the total cellular [Mg] ([Mg]t) could be observed

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in HEK293 cells overexpressing SLC41A1 (Kolisek et al. 2008). SLC41A1 activity was temperature-sensitive and insensitive to the Mg2+ channel blocker, cobalt(III) hexaammine (Kolisek et al. 2008). Thus, it has been concluded that SLC41A1 is a bona fide Mg2+ carrier mediating Mg2+ efflux (Kolisek et al. 2008). In follow-up work, Kolisek and colleagues, by using the fluorescent probe mag-fura-2 to measure [Mg2+]i changes in transgenic HEK293 cells with inducible overexpression of SLC41A1, demonstrated that SLC41A1-mediated Mg2+ efflux is strictly dependent on [Na+]e and reduced by 91% after complete replacement of Na+ with N-methyl-D-glucamine (Kolisek et al. 2012). Also imipramine and quinidine, known unspecific Na+/Mg2+ exchanger inhibitors, led to a strong 88–100% inhibition of SLC41A1-related Mg2+ extrusion (Kolisek et al. 2012). Furthermore, these authors have demonstrated the cAMP-mediated regulation of the transport activity of SLC41A1 via phosphorylation by cAMP-dependent protein kinase A. Thus, all together, it has been concluded that SLC41A1 met all the characteristics of the Na+/Mg2+ exchanger, which has been formerly described in many scientific reports before its molecular identity had been uncovered (Nishizawa et al. 2007; Romani 2007, 2011; Romani and Scarpa 2000; Delva et al. 2006; SchweigelRöntgen and Kolisek 2014; Günther 1993, 2006b, 2007; Fleig et al. 2013; Kolisek et al. 2012). The cytosolic N-terminal flanking region of SLC41A1 plays a key role in the regulation of SLC41A1 function and turnover. Not only it possesses multiple phosphorylation hotspots for various kinases, but Mandt and colleagues have also shown that the deletion of the cytosolic N-terminal sequence (92 amino acids long) of the protein suspends Mg2+-dependent regulation of SLC41A1-mediated Mg2+ transport via the endosomal protein recycling in the cell (Kolisek et al. 2012; Mandt et al. 2011). They have proposed a model, in which independent of [Mg2+]e, SLC41A1 is constitutively endocytically recycled from the cell surface. When the [Mg2+]i is low, recycling of endocytosed SLC41A1 to the cell surface is favored over degradation at the lysosome. When the [Mg2+]i is high, lysosomal degradation is favored (Mandt et al. 2011). However, this model is not coherent with the core function of SLC41A1, to conduct Mg2+ extrusion. If that were the case, it would mean that the cellular capacity to extrude Mg2+ increases with lowering [Mg2+]i, a rather strange thought. The importance of cAMP in regulation of SLC41A1-mediated Mg2+ efflux has been underlined by the work of Mastrototaro and colleagues (Mastrototaro et al. 2015). They have corroborated an inhibitory effect of insulin ([cAMP]i limiting hormone) on the SLC41A1-dependent Mg2+ efflux and clarified the role of the insulin signaling cascade with the end effector PDE3b (phosphodiesterase 3b) for regulation of the Mg2+extruder. Recently Sponder and colleagues correlated overexpression of SLC41A1 with the attenuation of pro-survival Akt/PKB–Erk1/2 signaling in HEK293, HeLa, and SH-SY5Y cells and thus, from the larger perspective, demonstrated that SLC41A1 expression status and [Mg2+]e (and consequently also [Mg2+]i) modulate the activity of kinases involved in anti-apoptotic and, hence, pro-survival events in cells (Sponder et al. 2017).

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SLC41A1 has been implicated in the pathoetiology of various disease conditions. Noteworthy is the chromosomal localization of SLC41A1 within the Parkinson disease (PD) susceptibility locus PARK16. Moreover, several PD-associated mutations have been detected in SLC41A1. Regarding PD, it is assumed that gain of function mutations (e.g., p.A350V) in SLC41A1 might contribute to an increased risk of developing PD and vice versa – loss of function mutations in the Mg2+ extruder might decrease the risk of developing PD (Kolisek et al. 2013a; Bai et al. 2017). Furthermore, SLC41A1 has also been associated with preeclampsia/eclampsia in pregnant women, kidney complications, diabetes mellitus, osteoporosis, and cardiovascular complications (Mastrototaro et al. 2015; Hurd et al. 2013; Kolisek et al. 2013b; Tsao et al. 2017; Yu et al. 2014).

4.7.2

KelI/XK

Although primarily expressed in erythroid tissues, Kell and XK are also present in many other tissues (Table 3) (Rivera et al. 2013; Lee et al. 2000). XK and Kell are linked close to the membrane surface by a single disulfide bond between Kell cysteine 72 and XK cysteine 347 (Fig. 1) (Lee et al. 2000). While Kell is an endothelin-3-converting enzyme, XK has structural characteristics of prokaryotic and eukaryotic transport proteins (Ho et al. 1994; Zhu et al. 2009). Rivera and colleagues studied the activity of Na+/Mg2+ exchanger in erythrocytes of Kell-KO, XK-KO, and Kell/XK-KO mice (Rivera et al. 2013). They found that Na+/Mg2+ exchange was significantly reduced by the absence of XK and increased in Kell-KO animals compared to wild-type mice. However, in Kell/XK-KO, the Na+/Mg2+ exchange activity resembled that of Kell-KO Na+/Mg2+ exchange activity suggesting that Kell may act as a Na+/Mg2+ exchanger regulatory unit (Rivera et al. 2013). Deletion or loss of function mutations within XK leads to McLeod syndrome. It is a rare and progressive disease that shares important similarities with Huntington disease but has widely varied neurologic, neuromuscular, and cardiologic manifestations. Patients with McLeod syndrome have a distinct hematologic presentation with specific transfusion requirements (Roulis et al. 2018).

4.7.3

NIPA1–NIPA4 (Non-imprinted in Prader-Willi/Angelman Syndrome 1–4)

The human NIPA family comprises four members, namely, NIPA1, NIPA2, NIPAL1 (NIPA3), and NIPAL4 (NIPA4). Members 1–4 (mouse) of the NIPA family have been characterized as putative Mg2+ transporters with channel-like properties when expressed in X. laevis oocytes and characterized with TEV and mag-fura-2-assisted fluorescence spectrometry (Table 1) (Quamme 2010; Goytain et al. 2007, 2008a). NIPA1–NIPA4 mediate Mg2+ uptake that is electrogenic,

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voltage-dependent, and saturable with a Km ¼ 0.31, 0.66, 0.9, and 0.36, respectively (Quamme 2010; Goytain et al. 2007, 2008a). All four NIPA proteins exhibit quite broad substrate specificity and thus behave like unspecific cation channels (Table 2) (Quamme 2010; Goytain et al. 2007, 2008a). NIPA1–NIPA4 seem to be ubiquitously expressed, but NIPA1 has its highest expression level in the brain (Table 3). The alteration of [Mg2+]i induces the redistribution of NIPA1 and NIPA2 between the endosomal compartment and the plasma membrane (Fig. 1). High [Mg2+]e results in diminished cell surface NIPA1 and NIPA2, whereas low [Mg2+]e leads to an accumulation of NIPA1 and NIPA2 in early endosomes and their recruitment to the plasma membrane (Quamme 2010; Goytain et al. 2007, 2008a). Unfortunately, all NIPA-related Mg2+ transport data have been acquired in a heterologous expression system, and thus we cannot exclude that NIPA1–NIPA4 do not transport Mg2+ in homologous expression systems. NIPA1 has been implicated in autosomal-dominant hereditary spastic paraplegia and NIPA2 in childhood absence epilepsy (Svenstrup et al. 2011; Xie et al. 2014). If the Mg2+ transport function of NIPA proteins is confirmed in a homologous expression system, this would represent direct evidence of the involvement of cellular Mg homeostasis in the pathoetiology of these serious neurological ailments.

4.8

MagT1 (Magnesium Transporter Subtype 1) and TUSC3/ N33 (Tumor Suppressor Candidate 3): Mg2+ Transporter Candidates Which Turned to Have Other but Not Mg2+ Transport Functions

MagT1 (magnesium transporter subtype 1) was screened among the magnesiotropic genes described by Goytain, Quamme, and colleagues (Quamme 2010; Goytain and Quamme 2005c). Its first functional characterization was produced by the same group. MagT1 expressed in X. laevis oocytes conducts the electrogenic transport of Mg2+ as revealed by TEV. Permeation of MagT1 is limited strictly to Mg2+ (Quamme 2010; Goytain and Quamme 2005c). Zhou and Clapham have demonstrated the plasma membrane localization of human MagT1 and its human homolog TUSC3/N33 (tumor suppressor candidate 3; found by in silico analysis, MagT1 and TUSC3 share 66% identity in the amino acid sequences) and have examined with whole-cell mode patch clamp net currents resulting from the overexpression of these proteins in HEK 293T cells. No MagT1 and/or TUSC3/N33-specific Mg2+ conductance has been recognized (Zhou and Clapham 2009). However, by using the new generation Mg2+ probe KMG-104 AM, these authors have demonstrated that siRNA-mediated MagT1 and/or TUSC3/N33 silencing leads to a reduction of the Mg2+ influx capacity. Interestingly, the knockdown of MagT1 results in about the same reduction of Mg2+ influx capacity as has been seen for TUSC3/N33; the simultaneous knockdown of both Mg2+ transporter candidates, namely, MagT1 and

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TUSC/N33, has no additive effect on the reduction of Mg2+ influx capacity of HEK293 cells (Zhou and Clapham 2009). Zhou and Clapham have also performed a functional complementation test and shown that, when expressed in the alr1Δ S. cerevisiae strain JS74B, human MagT1 and TUSC3/N33 sp.v. 2 can complement its growth deficiency upon the presence of normal Mg2+ in the cultivation medium (otherwise this strain proliferates only when 50–100 mM Mg2+ is provided to the cells) (Zhou and Clapham 2009). The sequences of MagT1 and TUSC3/N33 have no similarity to any known bacterial or eukaryotic (mammalian) genes encoding for Mg2+ transporters (Quamme 2010; Goytain and Quamme 2005c). MagT1 and TUSC3/N33 are orthologs of the yeast proteins Ost3 and Ost6 and have recently been found to be the oxidoreductase subunits of the ER-localized STT3B (catalytic subunit of the oligosaccharyltransferase (OST) complex) complex (Shrimal et al. 2015). The STT3B complex contains either MagT1 or TUSC3/N33, which have a role in substrate recruitment (Cherepanova et al. 2016; Mohorko et al. 2014). Obviously, the Mg2+ transport function and localization proposed for MagT1 and TUSC3/N33 by Goytain and Quamme or Zhou and Clapham are clearly not in agreement with their oxidoreductase function or being part of the ER-localized OST complex (Zhou and Clapham 2009; Quamme 2010). The bifunctionality of MagT1 and TUSC3/N33 as OST subunits and plasma membrane Mg2+ transporters is in conflict with the observation that MagT1 and TUSC3/N33 proteins are not detectable in STT3B(
/
) HEK293-derived cell line, as these OST subunits are unstable in the absence of STT3B (Cherepanova and Gilmore 2016). Currently, the most feasible explanation for the involvement of MagT1 and TUSC3/N33 proteins in cellular Mg homeostasis is the one offered by Cherepanova and colleagues who hypothesize that the link between MagT1 or TUSC3 expression and Mg homeostasis probably occurs by an indirect mechanism involving the STT3B-complexdependent glycosylation of a protein that is needed for Mg2+ transport activity (Cherepanova et al. 2016).

5 Summary Approximately two decades ago, no eukaryotic Mg2+ transporters/Mg2+ homeostatic factors had been identified at the molecular level. Today, we recognize about two dozen of them (either confirmed or putative) with their identities revealed to scientists and biomedical professionals. At first glance, this is a remarkable move forward, but is this true? Without a doubt, the identification of Mrs2, TRPM6/7, and the novel MgGs (mostly discovered and characterized by Goytain and Quamme) have brought “fresh breeze” and momentum to the field of Mg research that was, at that time, limited “only” to biochemical and physiological studies because of a lack of molecular targets and because no genetic manipulation, or in-depth characterization of molecular constituents of cellular Mg homeostasis were possible.

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However, with hindsight, the selection of X. laevis oocytes for the characterization of mammalian npMgTs (encoded by MgGs) in combination with TEV was not the best move. Unfortunately, not a single mammalian/human npMgT assumed to be an ion channel transporting Mg2+ (apart of other cations) based on TEV characterization in X. laevis oocytes has proven to be one in homologous expression systems. Thus, strictly speaking, out of the total of 24 candidate Mg2+ transporters/Mg2+ homeostatic factors, only approximately one third has been experimentally established as being directly involved in the Mg2+ homeostatic network of the cell, either as Mg2+ transporters or as Mg2+ homeostatic factors. The other two thirds have been studied only poorly, sometimes being limited to a single report. Some of the pnMgTs have over the time proven not to be Mg2+ transporters at all. For example, MagT1 and TUSC3/N33 are still often quoted as being Mg2+ channels, despite the fact that they have never been shown to be channels in a homologous expression system. Moreover, large amounts of solid evidence exist showing that MagT1 and TUSC3/N33 are oxidoreductases of the ER-localized OST complex. Nowadays, the proteins constituting the cytoplasmic membrane Mg2+ transport circuit (TRPM6/7 and SLC41A1; Fig. 6) and the mitochondrial (IMM) Mg2+ transport circuit (Mrs2, SLC41A3 and APC/SCaMC; Figs. 3 and 4) have been demonstrated by independent studies to be the primary constituents of the cellular Mg2+ homeostasis. They all act like Mg2+ transporters (channels, carriers/ exchangers). The position of CNNM2 and CNNM4 in cellular Mg2+ homeostasis is a matter of controversy, and the debate continues as to whether these proteins are Mg2+ transporters per se or whether they play the role of “true” Mg2+ homeostatic factors without the ability to transport Mg2+ (meaning sensors of [Mg2+]e and/or [Mg2+]i and regulators of other components of Mg2+ homeostatic network that are transporting Mg2+). Nevertheless, no doubt exists that CNNM2 is crucial for Mg2+ homeostasis at the level of the cell and also of the organism, as mutations in the gene encoding for CNNM2 have been identified that lead to severe systemic hypomagnesaemia and renal Mg2+ wasting. The other putative Mg2+ transporters/homeostatic factors described in this manuscript must be robustly researched before uncertainties can be lifted to enable a comprehensive elucidation of their functions with respect to cellular Mg2+ homeostasis. Acknowledgment Our gratitude is due to Dr. Theresa Jones for linguistic corrections. This work was supported by the grant “Return Home” issued by the Government of Slovak Republic to MK and also by the project “Creating a New Diagnostic Algorithm for Selected Cancer Diseases” (ITMS: 26220220022) co-financed from EU sources and the European Regional Development Fund. The authors declare no conflict of interests. All authors read and approved the final version of the manuscript.

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Contributions MK and GS wrote the manuscript, and IP, MC, ZT, TW, and PR contributed to the manuscript writing.

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Rev Physiol Biochem Pharmacol (2019) 176: 107–130 DOI: 10.1007/112_2018_11 © Springer International Publishing AG, part of Springer Nature 2018 Published online: 5 May 2018

Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and Radiotherapy-Associated Resistance Amir Abbas Momtazi-Borojeni, Jafar Mosafer, Banafsheh Nikfar, Mahnaz Ekhlasi-Hundrieser, Shahla Chaichian, Abolfazl Mehdizadehkashi, and Atefeh Vaezi

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Curcumin in the Treatment of Gynecological Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

The original version of this chapter was revised. A correction to this chapter is available at DOI: 10.1007/112_2018_14. A. A. Momtazi-Borojeni (*) Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran Department of Medical Biotechnology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran e-mail: [email protected]; [email protected] J. Mosafer Research Center of Advanced Technologies in Medicine, Torbat Heydarieh University of Medical Sciences, Torbat Heydarieh, Iran B. Nikfar (*) Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Iran University of Medical Sciences, Tehran, Iran e-mail: [email protected] M. Ekhlasi-Hundrieser Werlhof-Institut, Hannover, Germany S. Chaichian Minimally Invasive Techniques Research Center in Women, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran A. Mehdizadehkashi Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran A. Vaezi Department of Community Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

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3 4

Curcumin in Restoring Platinum Drug-Induced Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Evidences of Synergistic Anticancer Features of Curcumin and Paclitaxel In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Curcumin and Paclitaxel in the Form of Nanoformulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 The Radiosensitizing Function of Curcumin in Gynecological Cancers . . . . . . . . . . . . . . . . . 7 Approaches to Enhance Curcumin Anticancer Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Exploitation of Molecular Pathways Modulated by Curcumin in Gynecological Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Curcumin Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Curcumin Nanoformulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 114 116 118 119 120 122 123 125 126

Abstract The development of resistance toward current cancer therapy modalities is an ongoing challenge in gynecological cancers, especially ovarian and cervical malignancies that require further investigations in the context of drug- and irradiationinduced resistance. In this regard, curcumin has demonstrated beneficial and highly pleiotropic actions and increased the therapeutic efficiency of radiochemotherapy. The antiproliferative, anti-metastatic, anti-angiogenic, and anti-inflammatory effects of curcumin have been extensively reported in the literature, and it could also act as a chemopreventive agent which mitigates the out-of-target harmful impact of chemotherapeutics on surrounding normal tissues. The current review discussed the modulating influences of curcumin on some cell and molecular features, including the cell signaling and molecular pathways altered upon curcumin treatment, the expression of target genes involved in the progression of gynecological cancers, as well as the expression of genes accountable for the development of resistance toward common chemotherapeutics and radiotherapy. The cell molecular targets implicated in curcumin’s resensitizing effect, when used together with cisplatin, paclitaxel, and irradiation in gynecological cancers, are also addressed. Finally, rational approaches for improving the therapeutic benefits of curcumin, including curcumin derivatives with enhanced therapeutic efficacy, using nanoformulations to advance curcumin stability in physiological media and improve bioavailability have been elucidated. Keywords Cervical cancer · Cisplatin · Curcumin · Nanoformulation · Ovarian cancer · Paclitaxel

Abbreviations CDK COX-2 Cur DNMTs GSTs HDAC IAPs ICAM-1

Cyclin-dependent kinase Cyclooxygenase-2 Curcumin DNA methyltransferases Glutathione S-transferases Histone deacetylases Inhibitor of apoptosis family of proteins Intercellular adhesion molecule 1

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IKK iNOS MT P-gp PI3K VEGF

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IκB kinase Inducible nitric oxide synthase Metallothionein P-glycoprotein Phosphatidylinositide 3-kinase Vascular endothelial growth factor

1 Introduction Cancer is defined as the uncontrolled growth of particular cells inside an organism, where the outgrowth of cells eventually causes serious complications (Peng et al. 2003). Considering that cancer cells are derived from a normal cell or tissue following the accumulation of mutations imparting aggressive features, there is almost as many kinds of cancer cells as there are normal tissues (Abouzeid et al. 2014; Chen et al. 2015a; Ganta and Amiji 2009; Montopoli et al. 2009; Nessa et al. 2012; Peng et al. 2003). The prominent types of cancers are derived from tissues with high rate of cell division or great exposure to potential mitogenic compounds. According to the Global Burden of Disease Study (GBD), gynecological cancers and breast cancer are ranked among the top kinds of cancers causing death, together, both accounted for 4.29% mortality among women worldwide in 2017 (https:// vizhub.healthdata.org/gbd). Although the targeted treatment of cancer cells has remained a difficult task, thanks to the numerous attempts of scientists, the treatment modalities have greatly improved. In this regard, combined-therapy modalities have been shown to give superior successful results compared to single-treatment modalities in controlling different types of cancers, including gynecological cancers (Abouzeid et al. 2014; Aqil et al. 2017; Ganta and Amiji 2009; Huq et al. 2014; Punfa et al. 2012; Saengkrit et al. 2014; Sarisozen et al. 2014). The sequential mode of therapy in gynecological cancers begins with the surgical removal of tumors followed with radiotherapy and chemotherapy, to eliminate any remaining cancer cells. However, the management of cancer therapy faces difficulties upon relapse with more refractory tumors (Watson et al. 2010; Zaman et al. 2016; Zhang et al. 2017). For example, in ovarian cancer, more than 70% of the first diagnosed patients are found resistant to taxane treatment, and finally all of them are left resistant upon relapse (Watson et al. 2010). Although combination chemoradiotherapy improves the survival rate, it also increases the chance of dose-limiting toxicities (Watson et al. 2010). In this regard, curcumin, a polyphenol derived from Curcuma longa plant, has shown beneficial anti-inflammatory (Abdollahi et al. 2018; Aggarwal and Harikumar 2009; Momtazi-Borojeni et al. 2017), antitumor (Kuttan et al. 2007; Momtazi et al. 2016), anti-metastatic, antiangiogenic (Kuttan et al. 2007), antioxidant (Ak and Gülçin 2008), and chemopreventive (Duvoix et al. 2005; Kawamori et al. 1999; Rezaee et al. 2016) properties, when added to the current regimens. The molecular targets of curcumin are reportedly very diverse, including various kinases, gene modulators, transcription factors,

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varying growth factors, and cell membrane receptors (Hajavi et al. 2017; Kasinski et al. 2008; Pan et al. 2008; Soflaei et al. 2017; Watson et al. 2010; Zhang et al. 2017). Curcumin with very wide pleiotropic functions holds the key to modifying the trend of cancer therapy and advanced development of current cancer therapy modalities. Regarding gynecological cancers, curcumin has demonstrated opposing typical cervical cancer risk factors in advancing molecular alterations toward cancer incidence or progression, including human papilloma virus infections (typically HPV16 and 18), estrogen, smoking, and obesity (Maruthur et al. 2009; Zaman et al. 2016). For instance, it has been shown that curcumin could inhibit the expression of E6 and E7 oncoprotein, reduce estrogen-induced DNA damage, and mitigate adipose-related inflammation and estrogen production (Zaman et al. 2016). The current review presents an assortment of studies on curcumin ameliorating functions in gynecological cancer progression and metastasis. The sensitizing influence of curcumin treatment, when combined with routine chemotherapeutic agents like cisplatin and paclitaxel as well as irradiation, has been addressed, together with the molecular pathways associated with the drug-induced resistance which curcumin counteracts. Moreover, the approaches adopted to advance curcumin anticancer potential, stability, and bioavailability have also been discussed thoroughly in terms of effectiveness, which includes various curcumin formulations and curcumin derivatives.

2 Curcumin in the Treatment of Gynecological Cancers It has been shown that curcumin could act as an anti-metastatic agent and inhibit endometrial carcinoma (EC) cell migration and invasion in vitro through decreasing the expression and activity of the matrix metalloproteinases (MMP)-2 and MMP-9. These enzymes that degrade the extracellular matrix in tumors make the metastasis of cancer cells possible and are believed to drive deep myometrial cancer invasion and metastasis in lymph node in type II EC. The reduced expression of these enzymes by curcumin was also found to occur through suppression of the ERK signaling pathway (Chen et al. 2015b). Curcumin-induced apoptosis in ovarian cancer cells was found to be independent of p35, as it displayed the same cytotoxic activity in cells with reduced or knockdown p53 expression, as shown in the wild-type p53 cells. Nuclear condensation and fragmentation, DNA fragmentation, and poly(ADP-ribose) polymerase-1 cleavage were the cell features in HEY cells treated with curcumin which denoted cell apoptosis. Furthermore, it was found that both the intrinsic and extrinsic pathways of apoptosis could be activated by curcumin. The enhanced activity of p38 mitogen-activated protein kinases (MAPK) reduced the expression of antiapoptotic regulators of survivin and Bcl-2, and the suppression of prosurvival Akt signaling was also found to be involved in curcuminmediated anticancer cell death in various ovarian cancer cells (Watson et al. 2010). It has been shown that curcumin could partially suppress urokinase-type plasminogen activator (uPA) expression in the highly invasive human ovarian cancer cell line, HRA, which is involved in cancer cell metastasis. The expression of the

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serine protease uPA has been determined to be fed through Src-MAPK/ERK-PI3K/ Akt-NF-kB and the Src-MAPK/ERK-AP-1 pathways in response to TGF-B1, where curcumin is reported to only abrogate the formation of the AP-1 complex (Tanaka et al. 2004). Given the beneficial influences of curcumin in limiting invasive cancer cell progression, the use of curcumin in the commonly used therapy regimen for advanced gynecological cancer types could help to improve the outcome of therapy. This paper presents studies on gynecological cancerous tumors, in which curcumin addition has been demonstrated to improve the therapeutic window and oppose drug-resistant cancer cell types.

3 Curcumin in Restoring Platinum Drug-Induced Resistance Platinum drugs such as cisplatin and oxaliplatin are the first-line chemotherapeutics against ovarian, bladder, and testicular cancers, and their administrations are frequently faced with the development of resistant tumors (Montopoli et al. 2009). The loss of platinum uptake by cells through gated channel-facilitated diffusion, p53 gene implication in DNA damage repair, and enhanced intracellular level of glutathione, responsible for platinum inactivation and removal, are among the underlying mechanisms for the drug resistance. To evade the platinum drug-induced resistance, extensive studies have been conducted, in which a combination therapy with phytochemicals has been shown to be highly effective. In this regard, curcumin has been utilized in combination with platinum drugs like cisplatin and oxaliplatin to enhance their anticancer properties. It has been shown that curcumin could resensitize cisplatin-resistant ovarian cancer cells, and it suppresses DNA damage responses against these DNA crosslinking agents. It has been found that curcumin treatment downregulates the Fanconi anemia (FA)/BRCA pathway-related DNA damage repair responses, such as FANCD2 protein mono-ubiquitination, which is the prerequisite step for the DNA damage repair complex to form and relocate into chromatin of the DNA lesion sites (Chen et al. 2015a). Therefore, curcumin could reverse the acquired resistance in cancer cells, which lies in the enhanced activation of the FA/BRCA pathway, in response to DNA cross-linking agents in long-term administration (Fig. 1). Moreover, curcumin could suppress cisplatin resistance development through extracellular vesicle-mediated cell-cell communication. It is believed that the extracellular vesicles, known as exosome, transfer some proteins, mRNAs, and noncoding RNAs from donor cells to recipient cells, and this communication leads to the development of a drug-resistant cell population in various cancers (Zhang et al. 2017). Curcumin could limit such exosome-mediated chemoresistance by changing their contents. For instance, curcumin treatment has been shown to be accompanied with the restoration of MEG3 long noncoding (lnc) RNA levels (Fig. 1), upregulation of miR-29a and miR-185, and downregulation of miR-124

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Fig. 1 A conclusive view of main mediators in curcumin-mediated resensitizing platinum-resistant ovarian cancer cells. Curcumin has been found to restore platinum drug-induced resistance through suppressing the Fanconi anemia (FA)/BRCA pathway-related DNA damage repair responses, such as FANCD2 protein. Curcumin can also exert resensitizing effect through upregulation of MEG3 lncRNAs levels that inhibit drug resistance. Furthermore, curcumin enhances the ROS production via reduction of cellular levels of IL-6, NF-Kb, and GSH

and DNA methyl transferases (DNMTs) in cisplatin-resistant cells and exosomes, resulting in chemo-sensitization in A2780cp ovarian cancer cells. In this regard, curcumin-mediated overexpression of miR-29a and miR-185 has been shown to reduce DNMT1, 3A, and 3B levels and downregulate miR-124 expression, which is an mRNA regulator acting through the PTEN/Akt pathway and the P53/Nanog axis, and could reduce the survival of ovarian cancer cells, cisplatin resistance, and stem cell development (Zhang et al. 2017). Curcumin has been found to enhance the cell killing potential of chemotherapeutics by increasing the generation of reactive oxygen species (ROS) in cancer cells. It has been reported that curcumin could reduce the level of intracellular thiol of GSH, which is known to be involved in cisplatin deactivation (Yunos et al. 2011) (Fig. 1). It has been shown that pretreatment with cisplatin for 4 h before curcumin addition results in a synergistic cytotoxicity in some ovarian cancer cells, where curcumin could potentiate the ROS-mediated cell death triggered by cisplatin. The curcumin efficiency in suppression of cancer cell growth was found to be positively correlated with the basal levels of ROS in cancer cells. Interestingly, curcumin exhibited chemopreventive effect on normal tissues by activating the NF-kB

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pathway where the ROS intracellular level is decreased, whereas high curcumin concentrations (>15 μM) were found to enhance ROS levels in these tissues. Conversely, in cancer cells with previously high ROS concentrations, curcumin was shown to enhance ROS levels by inactivating the NF-kB pathway (Sreekanth et al. 2011; Yunos et al. 2011). Moreover, it appears that the reduced ROS and the increased GSH basal levels are the main hallmark of the development of resistance to cisplatin in cisplatin-resistant ovarian cancer cells, which could be linked to the more active NF-kB pathway in these cells. In summary, it is plausible for curcumin to contribute much greater to induce ROS generation in cisplatin-treated cancer cells than in non-treated ones, indicating that curcumin could act as a modifier in chemotherapy (Yunos et al. 2011) (Fig. 1). In addition to the NF-kB transcription factor discussed above, it was found that the expression of many other proteins was altered upon curcumin treatment (Nessa et al. 2012). A total of 59 proteins were found to be associated with platinum resistance in ovarian cancer cells, juxtaposing 2D gel electrophoresis from A2780 tumor model with that of resistant tumor cells (Huq et al. 2014). These included cytoskeletal proteins involved in cell invasion and metastasis, stress-related proteins and molecular chaperones, proteins involved in detoxification and metabolic processes, as well as a set of mRNA processing proteins (for a complete list, refer to Huq et al. 2014). The inhibition of inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) and enzymes (e.g., cyclooxygenase or COX-2 and inducible nitric oxide synthase or iNOS), suppression of angiogenic factors (e.g., vascular endothelial growth factor or VEGF), and modulation of other signaling proteins [e.g., the upregulation of serine/ threonine-specific protein kinase (AKT)] have also been reported in curcumintreated cancer cells (Nessa et al. 2012). It has also been shown that curcumin-mediated sensitization to cisplatin is associated with its anti-inflammatory activities in resistant cancer cells. It has been revealed that IL-6 reduction in curcumin-treated CAOV3 and SKOV3 ovarian cancer cell lines is accompanied by increased sensitivity to cisplatin, where it is believed that the overproduction of pro-inflammatory cytokines as such by the tumor cells drives drug resistance and tumor invasion (Chan et al. 2003). The production of IL-6 could also induce drug resistance in other cancer cells, including myeloma, lung, breast, prostate, and colon cancer cells. It has been found that multiple molecular targets are affected in IL-6-induced platinum resistance in various tumor cells. Mechanistically, IL-6 could reduce cisplatin accumulation in tumor cells through induction of multidrug-resistant proteins (MRPs) and P-glycoprotein (Pgp) in human hepatoma and renal carcinoma cells, induce the expression of glutathione S-transferase involved in ROS scavenging in breast cancer cells, and enhance the expression of metal-detoxifying protein of metallothionein in ovarian cancer cells. It has also been proposed to be involved in enhancing the invasiveness of ovarian cancer cells, where the induced transcription factor NF-kB results to the expression of additional inflammatory cytokines (Chan et al. 2003). The modulation of epigenetic regulators could lead to the emergence of cancer cells, where curcumin has also been shown to counteract them (Roy and Mukherjee 2014). In cervical cancer cases, the human papilloma virus is putatively known as

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the causative agent of cancer emergence and development, in which curcumin has been effective in suppressing the expression of viral oncoproteins of HPV-E6 and HPV-E7. Curcumin treatment has also been reported to mitigate cell molecular modulations derived from the activity of HPV-E6 and HPV-E7 proteins. Curcumin could inhibit p53 ubiquitin-dependent proteasomal degradation driven by HPV-E6 and act against HPV-E7-reduced pRb functionality. Curcumin could result in cell cycle arrest at the G1/S phase through the modification of regulatory proteins involved in cell cycle. It could inhibit the histone deacetylases (HDACs) that are activated by HPV. The acetylation and upregulation of p53 proteins; increased pRb, p21, and p27; and the corresponding suppression of cylin D1 and CDK4 have also been shown in both cisplatin-sensitive and cisplatin-resistant cancer cell line SiHa upon curcumin treatment, which are known to occur during cancer cell apoptosis (Roy and Mukherjee 2014). Figure 2 depicts the summary of the abovementioned multiple pathways and molecular targets where curcumin exerts opposing influence over cisplatin-induced resistance. In summary, it appears that curcumin is a modifier of multiple cellular pathways deregulated during cancer cell progression and, therefore, it could contribute to the advanced antiproliferative responses of other chemoagents applied for cervical and ovarian cancers. Such an improvement might hinder the development of resistance toward these agents. Paclitaxel is another chemotherapeutic agent that is administered for different sorts of gynecological cancers, and it has been shown that co-treatment with curcumin and paclitaxel could promote antitumor responses in comparison with paclitaxel alone. In this context, curcumin formulations could alter the expression of multiple cellular proteins and provide resistance to paclitaxel, which are discussed in the following two sections.

4 Molecular Evidences of Synergistic Anticancer Features of Curcumin and Paclitaxel In Vivo In a study conducted by Sreekanth et al. (Sreekanth et al. 2011), a comprehensive picture of the molecular evidences pertaining to the chemosensitizing effectiveness of liposomal curcumin in paclitaxel therapy has been presented, in which a curcumin liposomal formulation, consisting of phosphatidylcholine and cholesterol, was injected intraperitoneally every other day at a dose of 25 mg/kg to tumor-burden mice treated with paclitaxel (i.p. dose of 10 mg/kg, twice weekly). The tumors were mouse squamous cervical carcinoma model induced by 3-methylcholanthrene (3-MC), a carcinogen, and a xenograft model of a human cervical cancer (HeLa cells) in nonobese diabetic mice having severe combined immunodeficiency (NOD-SCID). It was found that the co-treatment with curcumin and paclitaxel resulted in a synergistic reduction in tumor emergence and tumor volume as compared to the single treatments. To determine the underlying cell and molecular mechanisms, a large collection of molecular targets were examined, including

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Cyclin D1, ICAM-1 VEGF MMP-2, MMP-9 Cox-2 Bcl-2 Survivin XIAP c-IAP

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Fig. 2 A summary of the molecular pathways by which curcumin treatment could lead to the sanitization of cancer cells in the cisplatin-induced resistant cancer cells. Curcumin could modulate the content of exosomes that contain molecular messengers driving the development of resistance toward cisplatin in the recipient cells (yellow sect). By inactivating the NF-kB pathway, curcumin could modify many molecular targets that are involved in cancer progression and metastasis (pink sect). Curcumin could reduce inflammatory cytokine secretion and the enzymes producing inflammatory compounds. Through IL-6 downregulation, moreover, curcumin could reduce the expression of metallothionein, glutathione S-transferase and P-glycoproteins, involved in the scavenging of superoxide radicals, drug detoxification, and drug efflux from cells, respectively (Green section). Finally, by counteracting HPV-E6 and HPV-E7 oncoprotein, curcumin could restore the level of antiapoptotic protein p53, inactivate histone deacetylase involved in chromatin condensation, and limit E2F transcription factor translocation to the nucleus, where the expression of target genes drives cell division and growth

the NF-kB activation status and the expression of NF-kB target genes involved in inflammation and tumor aggressiveness (such as Cox-2, ICAM-1, cyclin D1, VEGF, MMP-2, and MMP-9); the expression of antiapoptotic proteins that are transactivated by NF-kB (Bcl-2, c-IA P1, survivin, and XIAP); the expression and activation of three vital MAP kinases – i.e., c-Jun-NH2 kinase (JNK), extracellular signal-regulated protein kinase (ERK), and p38; as well as the cleavage and activity of procaspases 9, 8, 7, and 3. All these molecular evidences indicated that curcumin could tackle cancerous tumors by modulating various cell signaling pathways and kinases (Sreekanth et al. 2011), which could promote the efficiency of treatment in combination with paclitaxel. Similarly, it has been reported that the combination of curcumin (5 μM) and paclitaxel (5 nM) could augment anticancer responses more

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efficiently than paclitaxel alone in HeLa cells, without any synergistic effect on normal cervical cells, the 293 cell line (Bava et al. 2005). It has been proposed that the curcumin-induced sensitization to paclitaxel could be related to the opposite effect of curcumin on the NF-kB activation status. It was identified that curcumin could suppress NF-kB and Akt pathways, augment the activation of caspases and cytochrome c release. Moreover, it was discovered that curcumin opposed the NF-kB activation induced by paclitaxel and reduced the phosphorylation of Akt, which is a survival signal regulated by NF-kB (Bava et al. 2005). However, at low concentrations (5 μM), curcumin could not interfere with the tubulin-polymerization action of paclitaxel and could not further augment the cell cycle protein Cdc2, which increased during paclitaxel-induced mitotic arrest. This indicates that paclitaxelinduced resensitization by curcumin is independent of the classic function of taxols (or paclitaxel). To exert the abovementioned influences in cancer cells in vivo, it is required to improve the efficiency of drug delivery to these cells through the application of various drug delivery systems. Curcumin and paclitaxel have been shown to have poor pharmacokinetic profiles, which necessitates the use of appropriate formulations to help in attaining the required dose of the drug at tumor sites.

5 Curcumin and Paclitaxel in the Form of Nanoformulations According to the recent version of the National Comprehensive Cancer Network (NCCN) guidelines for cervical cancer, cisplatin and paclitaxel are recommended as the first-line combination therapy for cervical cancer metastasis (Li et al. 2017). However, the drug-related side effects (nephrotoxicity and hepatotoxicity) and development of resistance to the therapy have raised serious concerns in clinics (Li et al. 2017). As mentioned for cisplatin, some similar mechanisms are also accountable for the development of paclitaxel-induced resistance, including the upregulation of transmembrane-associated multidrug resistance proteins (P-gp, MRP-1, and ABCG2) and activation of major cell signaling pathways, most importantly, the NF-kB upregulation at the heart of many cellular responses related to cancer cell evasion. The upregulation of cytoprotective pathways like Akt and mitogen-activated protein kinase (MAPK), changes in the frequency of b-tubulin isotypes (Giannakakou et al. 1997; Yusuf et al. 2003), and changes in topoisomerase II (Topo IIa) activity and GST activities have also been reported for paclitaxelinduced resistance. Under these conditions, finding a chemopreventive agent like curcumin that could concomitantly confer cancer cell’s drug resensitization is the rational approach in dealing with invasive tumors. It has been shown that not only can curcumin reverse the multidrug resistance of cancer cells, it also could

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reduce the nephrotoxicity of paclitaxel, thereby enhancing the chemotherapeutic window. Similar findings have also been presumed for the paclitaxel and curcumin combination therapy, especially in the forms of various nanoformulations to enhance their stability and tumor delivery of these hydrophobic agents. Paclitaxelis is commonly prescribed against a wide spectrum of epithelial cancers (Sreekanth et al. 2011), where the hydrophobic nature of the drug promotes drug assimilation into tissues. However, when the drug is intended to reach a local tumor far from the injection site, hydrophobic chemoagents are required to be loaded in a vehicle with a hydrophilic outer layer to prevent the drug from rapid elimination and uptake by neighboring cells. The same strategy is also needed for the hydrophobic curcumin, where it is assumed to impart chemoprevention and chemo-sensitization in normal tissues and tumors, respectively (Ganta and Amiji 2009). Apart from cellular mechanisms of drug resistance and in vivo poor drug distribution, the high interstitial fluid pressure prevents the drug from moving toward cancer cells, where the presentation of the drug in the form of nanoformulation could overcome it (Abouzeid et al. 2014). Moreover, many researchers have attempted to apply various formulations, sometimes with excipients that impart some cellular modulating effect resulting to facilitated cell apoptosis (Ganta and Amiji 2009). For instance, it was reported that poly (ethylene oxide)-modified poly-(epsiloncaprolactone) (PEO-PCL) nanoparticles encapsulating paclitaxel (PTX) and C6ceramide, a lipid potentiating the apoptotic signal responses, could enhance both the efficiency of paclitaxel transfer to tumor and anticancer responses in SKOV3 human ovarian cancer cells in xenograft tumors, inoculated to female nu/nu mice. Through the encapsulation of curcumin along with paclitaxel in flaxseed oil containing nano-emulsion, it was found that curcumin could block NF-kB pathways and ABC transporter expression in both the wild-type and paclitaxel-resistant SKOV3 cells and enhance the death of cancer cells (Ganta and Amiji 2009). Furthermore, it has also been shown that the nano-emulsion, rich in omega-3 and omega-6 unsaturated fatty acids, promotes the cellular delivery of curcumin and paclitaxel. Although the author did not present any data regarding the residence time of curcumin and paclitaxel in the serum or blood and only focused on the mitigation of MDR features and cellular apoptosis, it was found that the nanoformulation was physically stable in size (~150 nm in diameter), and it could entrap large concentrations of paclitaxel and curcumin. Since both curcumin and paclitaxel are hydrophobic in nature, it was proposed that the inner oil phase could solubilize them and the outer hydrophilic shell of the droplets due to the presence of dense PEG chains, could enhance their physical stability, and apparently would promote drug delivery to tumor, if they are injected in vivo through the circulatory system (Ganta and Amiji 2009). The improved solubility and stability of paclitaxel and curcumin together with the slow drug release feature have also been reported for other types of nanoformulations, where the entrapment of drug in nanoparticles bypasses the drug efflux course regulated by MDR proteins and curcumin downregulates MDR proteins such as P-gp. For instance, Liu et al. developed a complex system of PLGA-phospholipidPEG nanoparticles (PLGA stands for poly-[lactic-co-glycolic]-acid polymer) from paclitaxel and curcumin, where nanoparticles comprised a PLGA core containing the

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drug and curcumin, the thin phospholipid interfacial layer, and the PEG hydrophilic outer layer. It has been found out that this system was more effective in controlling drug release compared to simple PLGA systems and could retain paclitaxel up to 72 h in PBS. Moreover, it has also been shown that the PLGA nanoparticles containing curcumin and paclitaxel are more efficacious in decreasing the expression of P-gp compared to free curcumin (Liu et al. 2016). Polyethylene glycolphosphatidylethanolamine (PEG-PE) micelles targeted with transferrin (TF) are another example of nanoparticles that have been used to promote paclitaxel and curcumin delivery to tumor sites and enhance the efficacy of tumor therapy. These micelles were evaluated against resistant ovarian cancers in a cancer cell culture grown in multicellular three-dimensional spheroids and in vivo tumors. When paclitaxel was co-delivered with curcumin in the form of micelles, an increase was recorded in the cytotoxicity of paclitaxel. In addition, transferrin modification of the micelles could assist in significantly deeper micelle penetration into the spheroids and tumors (Sarisozen et al. 2014). These studies all stated that curcumin could significantly enhance the antitumor potential of paclitaxel against resistant cancer cells, when curcumin is added into the chemotherapy regimen. Radiotherapy is also applied along with platinum-based agents in the treatment of advanced ovarian and cervical cancers. As previously discussed, curcumin could overcome these drug-induced resistances, and it has been shown to overcome radiotherapy-induced resistance as well.

6 The Radiosensitizing Function of Curcumin in Gynecological Cancers Radiation therapy is an efficient intervention to control cancer cell growth evasion and metastasis, especially when they are combined with chemotherapeutic agents capable of inducing radiosensitization such as carboplatin, cisplatin, 5-fluorouracil, ifosfamide, etoposide, and most taxanes. For instance, chemotherapy involving cisplatin and 5-fluorouracil is the present chemotherapy regimen for patients suffering stage IIA to IVA cervical cancer, which are administered together with radiotherapy. Although the combined chemoradiotherapy improves survival rate, such combination also increases the probability of chemotherapy-related toxicities including gastrointestinal and hematological toxicities. In this regard, the introduction of a safe agent like curcumin that is capable of inducing radiosensitization without a significant toxicity on normal tissues could enhance the therapeutic window and bring benefits for patients with advanced cervical cancers. Phase I clinical trials proved that the oral administration of curcumin is totally safe up to 12,000 mg/day (Javvadi et al. 2008; Lao et al. 2006) and could reduce histological lesions related to cancer evasion in some patients (Cheng et al. 2001). It has been shown that pretreatment with curcumin could enhance the cell growthinhibiting impact of radiotherapy in cervical carcinoma cells (HeLa and SiHa cells) and spare the normal fibroblast the trouble of increased radiation toxicity through a

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modulating intracellular ROS level (Javvadi et al. 2008). This is of importance as it has been shown that curcumin could act differently on normal and cancer cells, encouraging ROS generation in cancer cells while acting as antioxidant in normal cells. The elevated ROS in cancer cells could lead to the long-term activation of extracellular signal-regulated kinases (ERK1/ERK2) which encourage radiosensitization (Javvadi et al. 2008). Conversely, no evidence of NF-kB and Akt involvement in improving the irradiation therapy of cervical cancer cells was found on curcumin treatment, although curcumin has been shown to reduce the activity of NF-kB and Akt in prostate and colorectal cancers (Javvadi et al. 2008). Moreover, as explained above, curcumin has been shown to resensitize paclitaxelinduced resistant cells through the downregulation of NF-kB and Akt signaling pathways. These studies revealed that apparently, the downregulating effect of curcumin on these pathways is either dependent on cell type or therapy regime, although the implication of NF-kB and Akt activation in cancer cell survival has been firmly established. What is consistent is that the curcumin prooxidant activity could promote the anticancer effect of irradiation by contributing to induced ROS generation in cancer cells, regardless of cancer cell type or therapy regimen. Following their studies on the function of ROS in inducing cancer cell apoptosis (Javvadi et al. 2010; Javvadi et al. 2008), they pinpointed thioredoxin reductase-1 (TxnRd1), a cytosolic antioxidant enzyme scavenging IR-induced ROS, to mediate curcumin-sensitizing effect on irradiated cancer cells. They confirmed that the curcumin-mediated inhibition of TxnRd1 activity could result in increased radiosensitization in cancer cells, since TxnRd1 overexpression has been shown to terminate radiosensitization in cancer cells, in response to curcumin treatment (Fig. 3). Taken together, the pleiotropic function of curcumin on cancer cells and its diverse utility to be introduced in the treating schedule of different types of gynecological tumors, where curcumin by affecting a wide variety of cell signaling modulators, could counteract the phenomena responsible for the development of chemotherapy and/or IR-induced resistance in cancer cells, which is very common in these cancers. However, as earlier mentioned, the cancer-targeted functions of curcumin occur at high concentrations which are often very difficult to reach in tumors in vivo; therefore, an alternative set of investigations has focused on enhancing the efficiency of curcumin in cancer cell treatment.

7 Approaches to Enhance Curcumin Anticancer Efficacy Although curcumin’s multi-therapeutic function has drawn many researchers to investigate this polyphenolic compound, the insufficient therapeutic benefits of curcumin have prompted many researchers to look for various approaches to promote the anticancer potential of curcumin (Table 1). These include a set of investigations to enhance the pharmacokinetic profile of curcumin using various formulations, examination of curcumin analogs with the hope to discover derivatives

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Fig. 3 Curcumin-mediated radiosensitization in gynecological cancers. Curcumin can sensitize gynecological cancers to radiation therapy through inhibiting thioredoxin reductase-1 (TxnRd1) that is a cytosolic antioxidant enzyme scavenging IR-induced ROS

with more anticancer potency, and basic studies to unravel the molecular pathways modulated with curcumin treatment in order to find a combination therapy capable of tackling various malignancies.

8 Exploitation of Molecular Pathways Modulated by Curcumin in Gynecological Cancers It has been reported that the elevated levels of intracellular sphingosine/ceramides could promote curcumin-induced inhibition of cell growth and apoptosis in ovarian cancer cells (Yang et al. 2012). Sphingosine-1-phosphate, sphingosine, and ceramides are the metabolites of sphingolipids acting as messengers in cancer cell progression. While sphingosine/ceramides encourage cell apoptosis, sphingosine1-phosphate potentiates cancer cell survival, and the balance between sphingosine/ ceramides and sphingosine-1-phosphate determines the fate of cells. It has been shown that the curcumin-mediated cell apoptosis in ovarian cancer cells could be enhanced by the inhibition of sphingosine kinase-1 (SphK1) by the pharmacological inhibitor (SB 203580). Moreover, the inhibition of ceramide production by fumonisin B1 terminated the ShK1-induced cancer cell growth. As a result, the

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Table 1 Rational approaches to overcome curcumin insufficient efficacy in cervical and ovarian cancer cells Curcumin derivatives 3,5-bis (2-flurobenzylidene) piperidin-4-one

1,5-bis(22-hydroxyl)21,4pentadiene 1,5-bis(2-hydroxyphenyl)2 1,4-pentadiene-3-one

Dimethoxycurcumin Curcumin conjugation Curcumin-piperic acid Dipiperoyl and diglycinoyl curcumin

Curcumin-chlorogenic acid

Curcumin nanoformulations Liposomal curcumin

Niosomal curcumin

Milk-derived exosome PLGA nanoparticles conjugated to anti-Pgp proteins Naïve PLGA nanoparticles

Fe3O4 nanoparticles coated layer by layer with dextran and polylysine films

Description Increased cytotoxicity, inhibition of NF-kB nuclear translocation, TNF-ainduced IkB phosphorylation and degradation, and IKK inactivation In silico study proposed improved interaction with HPV16-E6 protein active site and p53 restoration Increased cytotoxicity, DNA fragmentation, and decreased HPV16and HPV18-associated E6 and E6 oncoproteins Increased cytotoxicity and downregulation of cyclin D1

Ref. Kasinski et al. (2008)

Singh and Misra (2013) Wang et al. (2011)

Wang et al. (2011)

In silico studies assumed increased toxicity in cervical cancers Increased cytotoxicity and ROS generation in histiocytoma cells, but it may be efficient against cervical and ovarian cancer cells? In silico study proposed increased cytotoxicity and HPV15-E6 downregulation

Mishra et al. (2005b) Mishra et al. (2005a)

Including DDAB, cholesterol, and a nonionic surfactant like Montanov82 increased cytotoxicity and cell penetration of curcumin Including nonionic surfactants of Span80, Tween80, and Poloxamer 188 enhanced cytotoxicity and controlled curcumin release Tumor growth inhibition following oral administration Targeted delivery of curcumin to cervical cancer cell line of KB-V1, expressing highly P-gp Enhanced cell apoptosis, reduced tumor burden, and suppressed HPV-E6 and HPV-E7 oncoprotein expression Enhanced curcumin entrapment in the particles, increased cell penetration, and enhanced cytotoxicity

Saengkrit et al. (2014)

Singh and Misra (2013)

Singh and Misra (2013)

Aqil et al. (2017) Punfa et al. (2012)

Zaman et al. (2016)

Kumar et al. (2014) and Mancarella et al. (2015)

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balance was shifted toward ceramide accumulation which pushes cancer cells toward apoptosis and may be useful to cumulatively enhance antiproliferative response in combination with curcumin. In addition to ceramide accumulation, curcumin has been shown to result in the modulations of other cell signaling molecules. It has been found that the activation of AMP-activated protein kinase (AMPK) could induce cell death and suppress cell progression in a variety of cancer cells, and CaOV3 ovarian cancer cell pretreatment with an AMPK inhibitor attenuates curcumin-induced cell death. Moreover, p38 activation and Akt inhibition are other changes which occur in apoptotic cancer cells treated with curcumin. Considering all the mentioned cell signaling effectors, every agent that could contribute to these modulations has been proven to enhance the anticancer potential of curcumin (Pan et al. 2008), and maybe their topical administration combined with curcumin as an ointment could exhibit therapeutic response in gynecological cancers that is worth being investigated.

9 Curcumin Derivatives Molecular docking studies of curcumin analogs with various functional group substitutions were conducted on prospective targets like EGFR tyrosine kinases, where the potential analogs were tested on various cancer cells with the hope of unraveling the relationship between curcumin structure and its activity (Sharma et al. 2015). Sometimes, these studies culminate in the discovery of more potent analogs as compared to curcumin. As discussed previously, the NF-kB signaling pathway plays a central role in governing cancer cell progression and metastasis, where curcumin has exhibited cancer-therapeutic values via NF-kB inactivation. In this regard, Kasinski et al. (2008) presented a synthetic monoketone analog of curcumin-termed 3,5-bis(2flurobenzylidene) piperidin-4-one – with enhanced anticancer activity against a variety of cancer cells, including ovarian and cervical cancer cells. In comparison with curcumin, this analog exhibited enhanced cancer cell growth inhibition up to tenfold in comparison with curcumin. Likewise, the analog rapidly inhibited the nuclear translocation of NF-kB at a dose tenfold lower than that of curcumin. In mechanism, NF-kB inhibition was found to result from the strong analog-IKK interaction which resulted in cancer cell apoptosis. 1,5-bis(22-hydroxyl)21,4-pentadiene, as a curcumin derivative lacking a diketone site and methoxy functional groups, has been found to exert more antiproliferative effect than curcumin on different cervical cancer cells (Singh and Misra 2013). The curcumin analog 1,5-bis(2-hydroxyphenyl)2 1,4-pentadiene-3-one could induce apoptosis more efficiently than curcumin, and it downregulates the expression of oncogenes E6 and E7 in HPV16- and HPV18-infected cervical cancer cells, known as risk factors of cervical cancers (Paulraj et al. 2015). It has been shown that dimethoxycurcumin is a more stable analog of curcumin in physiological media and could exert improved anticancer effect on multiple cervical cancer cells

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(Teymouri et al. 2018). These are shining examples of curcumin derivatives with enhanced efficacy, which begin with in silico studies on curcumin analogs with successful in vitro improved potency. However, the translation of such a potency to a real clinical setting is yet to be fully fulfilled. The low water stability and in vivo bioavailability of curcumin are the main setbacks of curcumin therapy. It has been shown that curcumin conjugation to hydrophilic molecules like amino acid, piperic acid, and chlorogenic acid could increase the stability of curcumin in physiological media (Singh and Misra 2013). Curcumin conjugation to piperic acid could enhance the cell penetrability of curcumin, and its administration with chlorogenic acid might fully restrict cancer cell proliferation in estrogen-responsive cervical cancer cells, where curcumin has been found to be partially effective in comparison (Mishra et al. 2005b; Singh and Misra 2013). Apart from the conjugation of curcumin to small molecules, it has been shown that curcumin entrapment in various nanoparticulate systems could improve its efficacy and tissue distribution in cervical and ovarian cancer cells, as discussed in the following section.

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Curcumin Nanoformulations

So far, a range of beneficial functions of curcumin has been presented, although much diverse biological actions remained unstated as they are out of scope in this review (Panahi et al. 2018; Teymouri et al. 2018; Teymouri et al. 2017). However, as already stated, there are some limitations associated with the therapeutic translation of curcumin in clinics such as low stability at physiological pH, hydrophobic nature, rapid elimination from circulation, hepatic metabolism, etc. (Aqil et al. 2017; Garcea et al. 2004). To overcome these limitations, there are numerous investigations, in which various lipid-based formulations and polymeric-based nanoparticles are utilized for curcumin delivery (Abouzeid et al. 2014; Aqil et al. 2017; Ganta and Amiji 2009; Kumar et al. 2014; Punfa et al. 2012; Saengkrit et al. 2014; Sarisozen et al. 2014; Xu et al. 2016). The list is very long, but as the scope of the current review is restricted to “curcumin in treating gynecological cancers,” this paper presented curcumin-loaded nanoparticles that have been tested against these cancers. It has been shown that lipid-based nanoparticles, including liposomes and niosomes, enhance curcumin stability in aqueous medium as they could accommodate hydrophobic curcumin in their membrane and prevent curcumin from degradation and precipitation (Saengkrit et al. 2014). In this regard, it has been shown that the nonionic surfactant (Montanov82®) could decrease liposomal curcumin agglomeration and restrict liposomal enlargement and precipitation in long-term storage. It could also enhance curcumin entrapment efficiency in liposomes. Likewise, the addition of cholesterol has also been reported to improve the entrapment efficiency of curcumin and limit the release of curcumin. Although introducing didecyldimethylammonium bromide (DDAB) imparts a positive charge to liposomes that increases cell uptake in vitro, positively charged liposomes have been

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determined to be rapidly removed by the neighboring blood cells at the injection site when they are intravenously administered. As a result, special consideration should be given to the route intended for liposomal curcumin administration. If liposomal curcumin is administered intravenously, where the liposomes are required to travel a long distance before they reach tumor and accumulate there, negative-to-neutralcharged liposomes would be probably more successful in reaching the tumor (Teymouri et al. 2016; Teymouri et al. 2015). However, when the intention is to enhance curcumin delivery via topical application, for example, as cream or an ointment in cervical cancers, positively charged liposomal curcumin would promote curcumin delivery to tissues as well as the therapeutic outcome due to increasing cell internalization of liposomal curcumin (Debata et al. 2013; Song and Kim 2006). Another issue that should be taken carefully into account is that the DDABcontaining liposomes per se have been proven toxic to both cancerous and normal cells. DDAB together with DOPE at DDAB/DOPE at 40 μM have been found to be potentially harmful to CasKi cells. It is necessary to investigate whether these liposomal components will cause unwanted suffering before deciding about their application in clinics, so as to avoid the possible undesired side effects (Saengkrit et al. 2014). The curcumin-niosome system has also been shown to possess high entrapment efficiency and lead to superior apoptotic rate in ovarian cancer A2780 cells compared with the free curcumin dispersed in dimethyl sulfoxide (Xu et al. 2016). The niosome system consisted of a nonionic surfactant of Span 80, Tween 80, and Poloxamer 80 plus additives of cholesterol was examined in terms of entrapment efficiency and curcumin delivery. It was found that the system is a highly superior version of liposomal curcumin in terms of curcumin entrapment efficiency. However, whether niosomal curcumin would be a safer and more successful delivery system, impart improved pharmacokinetic profiles, and result in higher tumor accumulation of curcumin than liposomal curcumin is an interesting contrastive study to be undertaken. Moreover, the surfactant-related hemolysis should be considered when optimizing these formulations of curcumin (Xu et al. 2016). Given such serious complications that liposome or noisome ingredients might carry for clinical application, searching for drug delivery systems that are perfectly safe is highly desirable. Milk-derived exosomes loaded with curcumin have been demonstrated to surpass the low bioavailability of oral curcumin and resulted in three to five times increased delivery of curcumin to various organs, as compared to free curcumin (Aqil et al. 2017). The exosomal curcumin exhibited increased antiproliferative and antiinflammatory activity against multiple cancer cell lines, including breast, lung, and cervical cancer cells. The underlying mechanism for the promoted efficacy of curcumin might lie in the fact that exosomes enter via endocytosis and go through the endosomal pathway, where curcumin activity would be preserved in the desirable acidic media of endosomes. Apart from this, exosomes alone have been shown to possess a moderate intrinsic antiproliferative and anti-inflammatory activity leading to tumor growth inhibition, which is hardly believed to be achieved by immune factors, miRNAs, and proteins derived from exosomes. Furthermore, high

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contents of proteins would provide a vast area of hydrophobic domains on the surfaces of exosomes for the lipophilic curcumin to interact and trap in exosomes. These exosomes were shown to protect curcumin from degradation throughout the gastrointestinal tract and enhance curcumin intake, indicating that exosomal curcumins are highly successful oral formulations (Aqil et al. 2017). Besides lipid-based nanoparticles, various polymer-based nanoparticles have been utilized to achieve the prolonged stability and enhanced efficacy of curcumin. For instance, PLGA-based curcumin nanoparticles have been reported to significantly decrease the tumor volume in an orthotopic mouse model of cervical cancer when it is injected intratumorally. The reduction of oncogenic miR-21, suppression of beta-catenin, and abrogation of E6/E7 HPV oncoproteins were found in tumor cells treated with curcumin-containing PLGA nanoparticles (Zaman et al. 2016). The surface modification of curcumin-containing PLGA nanoparticles like the attachment of anti-P-glycoproteins further enhanced curcumin delivery and cytotoxicity in the resistant cells overexpressing P-gp (Punfa et al. 2012). Poly(2-hydroxyethyl methacrylate) [PHEMA] with hydrophilic surface and Fe3O4 superparamagnetic nanoparticles (SPION) coated layer by layer with positively charged Poly(L-lysine) and negatively charged dextran is another example of polymer-based nanoparticles that has been applied for improving curcumin delivery to cervical cancer cells (Kumar et al. 2014; Mancarella et al. 2015). There are many other nanoparticulate systems and formulations that have been applied for improving curcumin delivery to various cancer cells, some tested in vitro and others in vivo (Teymouri et al. 2017). However, to determine which of these systems are fully applicable in clinic settings requires more in-depth investigation of curcumin nanoparticulate implications in cervical cancer tumors.

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Conclusion

The current review attempted to present an appropriate assortment of reports on the therapeutic and adjuvant potential of curcumin for resistant cancer malignancies, by placing emphasis on the studies conducted on gynecological cancers. The current chemotherapy and radiotherapy have frequently been reported to face refractory tumors upon relapse in ovarian and cervical cancers with a minor chance of treatment. In this regard, multiple cell and molecular evidences imply that curcumin could indeed resensitize the cells to chemotherapeutics and irradiation as evidenced by the enhanced therapeutic index of these regimens, when they are administered in combination with curcumin. These include suppression of the pathways involved in DNA damage repair, the inactivation of major transcription factors capable of promoting cell survival like NF-kB, AP-1, intracellular ROS elevation, downregulation of MDR-related proteins, and inhibition of inflammatory responses. Apart from these potential benefits of curcumin combination therapy, it was discussed that curcumin has the potential to act as an antitumor agent alone in these cancer types. Finally, various strategies of enhancing the therapeutic potency of curcumin ranging

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from alterations of curcumin molecular structure and curcumin encapsulation in varying nanoformulations have been presented in a hope to discover a more targetdirected approach to tumor eradication. Curcumin concentration in tissues and tumor is a defining factor with respect to the intrinsic ROS scavenging potency of cells. Therefore, it is highly important to investigate the therapeutic benefits of administering a given curcumin formulation combined with a chemodrug formulation followed by radiotherapy, to harness the cancer-treating potential of curcumin at most. Studies in this direction are highly necessary to translate the in vitro features of curcumin successfully into clinics, in managing the treatment of resistant cancer tumors of gynecological cancers. Acknowledgment The authors would like to say special thanks to Dr. Amir Saberi-Demneh and Dr. Leila Ghalichi for their guidance and kindness. Conflict of Interest The authors declare that they have no conflicts of interest about this report.

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Rev Physiol Biochem Pharmacol (2019) 176: 131–132 DOI: 10.1007/112_2018_14 © Springer International Publishing AG, part of Springer Nature 2018 Published online: 8 December 2018

Correction to: Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drug- and RadiotherapyAssociated Resistance Amir Abbas Momtazi-Borojeni, Jafar Mosafer, Banafsheh Nikfar, Mahnaz Ekhlasi-Hundrieser, Shahla Chaichian, Abolfazl Mehdizadehkashi, and Atefeh Vaezi

Correction to: Chapter “Curcumin in Advancing Treatment for Gynecological Cancers with Developed Drugand Radiotherapy-Associated Resistance” in: A. A. Momtazi-Borojeni et al., Rev Physiol Biochem Pharmacol, DOI: 10.1007/112_2018_11 The affiliation of the 6th author Dr. Abolfazl Mehdizadehkashi was incorrect. It has been corrected to Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran.

The updated online version of this chapter can be found at DOI: 10.1007/112_2018_11