Mini-Reviews in Medicinal Chemistry Beauvericin, A Fusarium Mycotoxin: Anticancer Activity, Mechanisms, and Human Exposure Risk Assessment

Table of contents :
Abstract:
Keywords:
1. INTRODUCTION
Fig. (1).
2. SOURCES
3. THE ANTICANCER ACTIVITY OF BEA
4. HEALTH RISK FROM EXPOSURE
Table 1.
Fig. (2).
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES

Citation preview

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REVIEW ARTICLE ISSN: 1389-5575 eISSN: 1875-5607

Beauvericin, A Fusarium Mycotoxin: Anticancer Activity, Mechanisms, and Human Exposure Risk Assessment

Impact Factor: 2.645

BENTHAM SCIENCE

Mini-Reviews in Medicinal Chemistry

Qinghua Wu1, Jiri Patocka2,3 and Kamil Kuca4* 1

College of Life Science, Institute of Biomedicine, Yangtze University, Jingzhou 434025, China; 2Institute of Radiology, Toxicology and Civil Protection, Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice, Ceske Budejovice, Czech Republic; 3Biomedical Research Centre, University Hospital, Hradec Kralove, Czech Republic; 4Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic

ARTICLE HISTORY

Received: September 09, 2017 Revised: April 19, 2018 Accepted: April 22, 2018

DOI: 10.2174/1389557518666180928161808

Abstract: Beauvericin (BEA) is a cyclic hexadepsipeptide, which derives from Cordyceps cicadae. It is also produced by Fusarium species, which are parasitic to maize, wheat, rice and other important commodities. BEA increases ion permeability in biological membranes by forming a complex with essential cations, which may affect ionic homeostasis. Its ion-complexing capability allows BEA to transport alkaline earth metal and alkali metal ions across cell membranes. Importantly, increasing lines of evidence show that BEA has an anticancer effect and can be potentially used in cancer therapeutics. Normally, BEA performs the anticancer effect due to the induced cancer cell apoptosis via a reactive oxygen species-dependent pathway. Moreover, BEA increases the intracellular Ca2+ levels and subsequently regulates the activity of a series of signalling pathways including MAPK, JAK/STAT, and NF-κB, and finally causes cancer cell apoptosis. In vivo studies further show that BEA reduces tumour volumes and weights. BEA especially targets differentiated and invasive cancer types. Currently, the anticancer activity of BEA is a hot topic; however, there is no review article to discuss the anticancer activity of BEA. Therefore, in this review, we have mainly summarized the anticancer activity of BEA and thoroughly discussed its underlying mechanisms. In addition, the human exposure risk assessment of BEA is also discussed. We hope that this review will provide further information for understanding the anticancer mechanisms of BEA.

Keywords: Beauvericin, anticancer, oxidative stress, signaling pathway, health risk, BEA.

1. INTRODUCTION Beauvericin (BEA) is a cyclic hexadepsipeptide composed of three units of phenylalanine and three units of 2hydroxyisovaleric acid (Fig. 1). BEA was firstly discovered in the entomopathogenic fungi Beauveria bassiana and Fusarium fungi [1, 2]. BEA (C45H57N3O9) forms needle-like crystals, is soluble in methanol, diethyl ether and chloroform, is slightly soluble in water, and has a melting point of 95-97°C [3]. Many pharmacological studies suggest that BEA has a broad spectrum of biological effects, such as insecticidal [4], antiviral [5] and antimicrobial [6]. The antimicrobial results showed that this cyclodepsipeptide has an *Address correspondence to this author at the Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic; Tel: +420605289160; Email: [email protected]

1875-5607/19 $58.00+.00

inhibitory effect on the human pathogenic microbes Candida albicans, Escherichia coli and Staphylococcus aureus [6]. In particular, BEA exhibits the strongest antimicrobial activity against S. aureus with MIC values of 3.91 μM [6]. However, BEA is also toxic to human and animal tissues and cells [7, 8]. Recently, Svingen e al. [9] showed that BEA exhibits significant cytotoxicity at a concentration lower than that for aflatoxin B1, which is the archetypal acute hepatotoxic and liver-carcinogenic mycotoxin. Oxidative stress is the underlying mechanism of the toxicity of BEA. It induces reactive oxygen species (ROS) generation and leads to an increase in oxidative stress, which causes cell apoptosis [10]. It is noteworthy that BEA is especially cytotoxic to cancer cells [11]. It inhibits drug efflux pumps and bone resorption, and is non-mutagenic, which suggests it as a potential drug candidate to fight disseminated cancer [11-13].

© 2019 Bentham Science Publishers

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will improve our further understanding of the anticancer mechanisms of BEA.

N O

2. SOURCES

O O O N

O O

N

O O O

Fig. (1). The chemical structure of beauvericin.

Indeed, increasing lines of evidence show that BEA can be potentially used in cancer therapeutics [5, 14-17]. For example, using different cancer cell lines (e.g. human leukaemia cell (CCRF-CEM), human non-small cell lung cancer (NSCLC) A549 cells, metastatic prostate cancer (PC-3M), and breast cancer (MDA-MB-231) cells), researchers found that BEA has a promising anticancer activity and may be useful for the development of new chemical compounds in cancer therapy [5, 16, 18]. Currently, the in vivo anticancer test of BEA is limited but, nevertheless, in a very recent in vivo study, BEA was detected in the tumour tissues and reduced the tumour volumes and weights in mice bearing murine CT-26 or human KB-3-1-grafted tumours [19]. Basically, BEA kills the cancer cells due to induced cancer cell apoptosis, necrotic cell death and oxidative stress [10, 16, 17]. Some studies further show that BEA induces apoptosis by decreasing the mitochondrial membrane potential (ΔΨm), which leads to the release of cyt c into the cytosol and caspase-3 activation. Moreover, this mycotoxin could regulate the activity of a series of signalling pathways to produce cell apoptosis. For example, it can reduce the expression of NF-κB, but increase the activity of JNK [20]. Moreover, other signalling pathways, such as JAK/STAT, TNF-α, and ERK are also involved in this context [15, 21]. In addition, intracellular calcium (Ca2+) plays an important role as a mediator in cancer cell death signalling induced by BEA [5]. BEA increases the intracellular Ca2+ concentration, which subsequently activates the expression of the different signalling pathways, induces oxidative stress and finally cell apoptosis [5, 22, 23]. However, the mechanisms underlying the connection between Ca2+ and the activation of the pathways are still poorly understood. Currently, the studies of the anticancer activity of BEA are scattered; moreover, there is no recent review article available to summarize the anticancer activity of BEA and discuss its underlying mechanisms. Thus, in this review, we have mainly summarized the anticancer activity of BEA both in vitro and in vivo. Moreover, its underlying mechanisms are thoroughly analysed from the viewpoint of apoptosis, oxidative stress, the Ca2+ model and signalling pathways. Some potential and promising research directions in this context are provided as well. Finally, the human exposure risk assessment of BEA is discussed. We hope that this review

BEA was first isolated from the entomopathogenic fungus Beauveria bassiana [1], but was later found as the secondary metabolite of many other microphytes [23, 24]. As one of the chemical contaminants, BEA was detected in maize kernels and derived products infected by phytopathogenic fungi, including Aspergillus [25], Cordyceps [26] and Fusarium species [27, 28]. Recently, the fermentation conditions of BEA production have been optimized on a large scale for application in the laboratory and industry [29, 30]. 3. THE ANTICANCER ACTIVITY OF BEA Currently, the investigation of the anticancer potential of BEA is a hot topic [15, 31]. BEA was shown to inhibit the migration of metastatic prostate cancer (PC-3M) and breast cancer (MDA-MB-231) cells, and exhibited antiangiogenic activity in HUVEC-2 cells [31]. In recent years, targeting cell motility has attracted attention as one of the alternative strategies for the development of anticancer therapies [14, 32, 33]. Cell motility is a critical cause of tissue invasion allowing primary tumours to disseminate and metastasize [33]. Thus, it is important to find new anticancer compounds with the ability to inhibit cell motility. Zhan et al. [14] showed that BEA inhibited the migration of metastatic prostate cancer (PC-3M) and breast cancer (MDA-MB-231) cells, and showed antiangiogenic activity in HUVEC-2 cells at sublethal concentrations. Thus, in this chapter, the anticancer activity of BEA and its underlying mechanisms is thoroughly discussed based on the currently available data. 3.1. The Role of Apoptosis in the Anticancer Activity of BEA It is clear that apoptosis is involved in the anticancer mechanisms of BEA [5, 15-17]. Actually, BEA induces cell apoptosis in different systems [3]. Tolleson et al. [34] reported its apoptotic activity in neonatal human keratinocytes and human oesophagal epithelial cells. Kegvi et al. [35] documented similar results with a porcine kidney epithelial cell line. BEA could also affect the immune functions by inducing the apoptosis of lymphocytes [36]. Moreover, the apoptosis induced by BEA was also observed in a human carcinoma cell line [5, 15, 16], rodent cholangiocytes [17], and porcine kidney PK15 cells [37]. BEA induced caspase-3 activity in a concentration- and time-dependent manner [37]. The anticancer activities of BEA have mainly been studied by the working group of Jow [5, 16, 38, 39]. During their investigation, BEA was reported to induce human leukaemia cell (CCRF-CEM) death [5]. Moreover, the BEA-induced cell death underwent an apoptotic pathway on the basis of an increase in cyt c release from the mitochondria and an increase of caspase-3/9 activity. BEA was also reported to induce the apoptosis of human Non-Small Cell Lung Cancer (NSCLC) A549 cells [16], KB and KBv200 cells [18]. Moreover, from the study by Lin et al. [16], the induction of apoptosis by BEA involves multiple cellular/molecular pathways. In their study, the treatment of human Non-Small

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Cell Lung Cancer (NSCLC) A549 cell with BEA activates a cell death pathway that regulates the mitochondrial membrane permeability by the down-regulation of p-Bcl-2 and the up-regulation of Bax, Bak and p-Bad, as well as inducing cyt c release. In addition, BEA induced caspase 3 activation and led to apoptosis [16]. Anticancer drugs, effective on both sensitive and MultiDrug Resistance (MDR) cells are regarded as the available method for overcoming MDR [40]. It is noteworthy that the mycotoxin BEA can inhibit the growth of the human epidermoid carcinoma cell line and induce apoptosis through the mitochondrial pathway, including sensitive KB and MDR KBv200 cells [18]. In the study by Tao et al. [18], BEA induced human epidermoid carcinoma cell apoptosis through the mitochondrial pathway, including a decrease in ROS generation, loss of ΔΨm, release of cyt c, and the activation of caspase-3/9. However, in this study, the regulation of Bcl-2 or Bax was not involved in the apoptosis induced by BEA [18]. Indeed, cell apoptosis is usually correlated with mitochondrial damage [41-43]. In the study by Tonshin et al. [44], BEA depleted the ΔΨm, uncoupled oxidative phosphorylation, induced mitochondrial swelling and decreased the Ca2+ retention capacity of the mitochondria. Moreover, the mitochondrial effects were strongly connected to the potassium ionophoric activity of the BEA. These results indicate that the cellular toxicity targets of BEA are the mitochondrion and the homeostasis of potassium ions [44]. 3.2. Oxidative Stress in the Anticancer Activity of BEA Another mechanism of the anticancer activity of BEA is oxidative stress. BEA could induce lipid peroxidation (TBARS) and intracellular glutathione (GSH) in porcine kidney epithelial cells (PK15) [45]. ROS and malondialdehyde (MDA) were also generated when the cells were exposed to BEA, suggesting ROS generation and oxidative stress are the potential mechanisms of BEA-mediated toxicity [10]. In another study [46], after BEA exposure, a decrease in reduced GSH levels and an increase in oxidized GSH was observed in human colon adenocarcinoma (Caco2) cells. The ROS level was significantly increased at an early stage. Moreover, BEA-induced cell death by a mitochondria-dependent apoptotic process with the loss of the ΔΨm. Based on the data obtained from [46], it could be hypothesized that BEA can exert anticancer effects by means of a ROS-dependent pathway. Cells exhibit mitochondrial dysfunction that can lead to a stable depolarized state of ΔΨm and cell death. Moreover, ROS generation with the alteration of GSH content leads to an increase in oxidative stress, which causes apoptosis in Caco-2 cells. Normally, the ROS and DNA damage lead to apoptotic cell death [47, 48]. However, Dornetshuber et al. [49] showed that ROS and DNA damage are not key factors in BEA-mediated cytotoxicity since, in their studies, oxidative stress does not contribute to BEA-induced cytotoxicity. Moreover, the potent cytotoxic activity of BEA was independent of cellular mismatch and nucleotide excision repair pathways. Therefore, the role of oxidative stress in the BEAinduced apoptotic cell death still needs further study.

Wu et al.

3.3. The Role of Calcium in the Anticancer Activity of BEA Ca2+, as one of the major signal molecules, regulates various aspects of cell functions including cell cycle progression, arrest and apoptosis in a wide variety of cells [50, 51]. It has been demonstrated that the transfer of Ca2+ from the endoplasmic reticulum to the mitochondria is required for the initiation of apoptosis [52]. Importantly, emerging evidence shows that Ca2+ has a close connection with autophagy and tumorigenesis [51-54]. BEA has been shown to activate platelets by increasing the cytoplasmic Ca2+ concentration [22]. However, it requires further investigation to identify whether the increase of intracellular Ca2+ plays an important role in the apoptotic pathway to BEA action. Jow et al. [5] showed that BEA induced human leukaemia cell (CCRFCEM) death. Moreover, BEA increased cytosolic caspase-3 activity and the release of cyt c from mitochondria. Blocking Ca2+ transduction greatly reduced BEA-induced cell death, indicating that intracellular Ca2+ plays an important role, maybe as a mediator in cell death signalling. In a subsequent study [39], the effect of BEA on Ca2+ concentration and the underlying mechanisms responsible for the changes of Ca2+ concentration in CCRF-CEM cells were further investigated. Indeed, BEA caused a rapid and sustained Ca2+ concentration rise in a dose-dependent manner. Excess extracellular Ca2+ facilitated a BEA-induced Ca2+ concentration rise by adding CaCl2. It is noteworthy that neither the voltagedependent Ca2+ channel blocker, nor the depletion of intracellular Ca2+, has any effect on BEA-induced Ca2+ concentration rise. Thus, BEA acts as a potent Ca2+ mobilizer by stimulating the extracellular Ca2+ influx and induces cancer cell apoptosis [39]. Similarly, BEA was found to activate Ca2+-activated Clcurrents and induces cell death in Xenopus Oocytes via the influx of extracellular Ca2+ [38]. In addition, BEA can stimulate Ca2+ entry with subsequent cell membrane scrambling and the inhibition of Ca2+ activated K+ channels with the blunting of cell shrinkage [12]. Therefore, the ability of BEA to increase the cytoplasmic Ca2+ concentration plays an important role in the induction of cancer cell apoptosis [5]. BEA-induced apoptotic changes such as DNA fragmentation have been demonstrated to take place in the complete absence of extracellular Ca2+ [55], suggesting that BEA triggers the release of Ca2+ from internal Ca2+ stores. In fact, BEA has been regarded as an apoptotic agent that releases Ca2+ exclusively from the endoplasmic reticulum [38, 56]. BEA induces the stimulation of Ca2+ entry with cell membrane scrambling and the inhibition of Ca2+ activated K+ channels with the blunting of cell shrinkage [12]. The exact mechanism of the Ca2+ in the BEAinduced cell apoptosis still needs further study. 3.4. Signalling Pathways that Participate in the Anticancer Activity of BEA Based on recent studies, a series of signalling pathways are clearly involved in the molecular mechanisms of the anticancer activity of BEA [15, 20]. Recently, Wätjen et al. [20] studied the anticancer potential of BEA and its underlying mechanisms using different cancer cell lines (HepG2, C6, Hct116, and H4IIE). As a molecular mechanism of cell

Beauvericin, A Fusarium Mycotoxin: Anticancer Activity

death, necrosis was detected in C6 glioma cells, whereas apoptosis prevails in H4IIE hepatoma cells. In H4IIE cells, BEA rapidly decreased the phosphorylation of ERK and strongly increased JNK phosphorylation. Moreover, a strong inhibition of NF-κB signalling was detectable in H4IIE cells. In addition, a series of protein kinases involved in signal transduction pathways showed a selective inhibition of src kinase by BEA [20]. In another study, BEA-induced cell apoptosis through the MAPK pathway in human non-small cell lung cancer A549 cells [15]. Moreover, the MEK1/2-ERK42/44-90RSK crosstalk signalling pathway plays an important role in BEAinduced apoptosis in human NSCLC A549 cancer cells [15]. In vivo, BEA decreased the serum levels of TNF-α and IFNγ in mice with experimental colitis. BEA suppressed T-cell proliferation, activation and IFN-γ-STAT1-T-bet signalling and subsequently led to the apoptosis of activated T cells by suppressing Bcl-2 and p-Bad, as well as increasing the cleavage of caspase-3, -9, -12 and PARP [21]. Compared with trichothecene mycotoxins [47], the study of the signalling pathway that participates in the BEA-induced cancer cell death is currently still limited. Therefore, in the future, more studies on the signalling pathways in BEA cytotoxicity are warranted. 3.5. In vivo Cases of BEA Anticancer Activity Almost all of the above conclusions are reached using in vitro studies using various cancer cell lines, but we know that the in vitro results are not always fully in accordance with the in vivo data [57,58]. Thus, in vivo studies using animal models to study the anticancer activity of BEA are urgently needed. Actually, only one in vivo study has been carried out so far and this further identified the promising anticancer potential of this mycotoxin in clinical usage [19]. Very recently, Heilos et al. [19] tested the in vivo anticancer effects of BEA by treating BALB/c and CB-17/SCID mice bearing murine CT-26 or human KB-3-1-grafted tumours, respectively. In addition to a more pronounced activity against malignant cells, BEA decreased tumour volumes and weights in BEA-treated mice. Moreover, BEA targets especially differentiated and invasive cancer types. A significant increase in necrotic areas within the whole tumour sections of BEA-treated mice was found. Furthermore, moderate BEA accumulation was detected in tumour tissues. In cervix carcinoma cells, G0/G1 phase arrest was detected with subtoxic concentrations of BEA, followed by apoptosis induction followed by the activation of the mitochondrial cell death pathway. Thus, combined with the previous in vitro data, this suggests that BEA should be a promising novel natural compound for anticancer therapy. In summary, BEA performs its anticancer activity mainly due to induced cancer cell apoptosis. BEA regulates the Bcl2 and Bax expression, decreases mitochondrial function and decreases the Ca2+ retention capacity of the mitochondria. Moreover, BEA exerts its anticancer effects by means of a ROS-dependent pathway. BEA-induced high-level intracellular Ca2+ plays an important role in cancer cell death. However, the exact mechanisms of Ca2+ in the BEA-induced cancer cell apoptosis still need further investigation. In addition,

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some signalling pathways are involved in the molecular mechanisms of the BEA anticancer activity. BEA can downregulate NF-κB signalling and up-regulate JNK phosphorylation. The JAK/STAT pathway also participates in this context. However, compared with other mycotoxins, including trichothecenes and ochratoxins, the information of the signalling pathway of BEA is still quite limited and needs further study. It is noteworthy that most of the anticancer studies involving BEA are carried out in vitro using cancer cell lines. However, so far, we have seen very little in vivo data on the anticancer effects of BEA. Information on the in vivo anticancer activity of BEA is urgently needed, since we need to know that whether BEA is stable and active in the body. Moreover, the toxicity of this product is an important issue for consideration. On the other hand, toxin-carrying monoclonal antibodies (mAb) that target proteins which only occur on the cancer cell surface are shown to be a promising way to treat cancer [59-61]. Indeed, it has already been demonstrated that mAb conjugated with trichothecene mycotoxin T-2 toxin are quite efficient cancer immunotherapies [47, 62, 63]. Therefore, the study of the BEA-mAb should be a promising strategy in anticancer therapies. However, there is still no data on the anticancer activity of BEA-mAb in vitro and in vivo. Moreover, autophagy is a basic metabolic process that is essential for cell survival and tissue homeostasis [64]. Currently, the regulation of autophagy in some mycotoxins (e.g. trichothecenes) has already been reported [23, 47]; the autophagy study, however, has never been performed on the mycotoxin BEA. Thus, whether or not BEA inhibits cancer cell autophagy, this scientific problem needs to be solved in the future. The studies of the anticancer activity of BEA are summarized in Table 1. The speculated mechanisms of the anticancer activity of BEA are shown in Fig. (2). 4. HEALTH RISK FROM EXPOSURE Fusarium spp., which produces BEA, colonize important cereal grains, such as corn, wheat and rice and may have an adverse impact on human and animal health [65]. Despite a limited amount of data regarding the occurrence of BEA in grain, this mycotoxin is a common food and feed contaminant with concentrations ranging from trace levels up to 520 mg/kg [66, 67]. The contamination of BEA in cereals was reported in different countries [68-71]. BEA was purified from corn kernel cultures of F. proliferatum and F. Moniliforme, isolated from corn ear rot in north Italy [68, 69]. F. poae can produce high amounts of BEA (2655 μg/kg) in wheat from north Italy. BEA (10-532 μg/kg) was produced by F. subglutinans in maize from Germany, Poland, Austria, Switzerland and Slovakia [70]. BEA levels varied between 3.8 and 26.3 mg/kg in rice on the Moroccan retail markets [71]. BEA was detected in maize harvested in Mexico (in 2003) with levels ranging from 300 to 400 mg/kg [65]. Moreover, BEA is reported to be common in Danish cereals and shows high hepatotoxicity on a high-content imaging platform [9]. Streit et al. [72] analysed 83 samples of feed and feed raw materials and found that BEA was the most

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Table 1.

Wu et al.

A summary of the anticancer activity of BEA in vitro and in vivo. Targets

Human acute lymphoblastic leukemia cells (CCRF-CEM cells) Human non-small cell lung cancer (NSCLC) A549 cells Prostate cancer (PC3M) cells; breast cancer (MDA-MB-231) cells; HUVEC-2 cells

Rat Liver mitochondria

HepG2, C6, Hct116, and H4IIE

KB and KBv200 cells

Human NSCLC A549 cells

RAW264.7 and HEK293 cells

Mice

Dose

Time

Major Results and Mechanisms

Conclusion

Refs.

24 hours

BEA increased caspase-3 activity, increased release of cyt c; cell death was reduced once reduced the Ca2+ level.

BEA induces the CCRF-CEM cell death mainly due to the apoptotic pathway, and intracellular Ca2+ plays an important role.

[5]

1-30 μM

24 hours

BEA upregulated Bax, Bak, and p-Bad; down regulated Bcl-2; mitochondrial membrane potential decreased, cyt c released increased; caspase 3 activity increased.

Bcl-2, mitochondrial membrane potential, cyt c, and caspase 3 participates in the BEA-induced apoptosis in human NSCLC A5349 cells.

[16]

2-7.5 μM

16-40 hous

BEA was cytotoxic to these cancer cells, and inhibited the endothelial HUVEC-2 cell network formation.

BE inhibited migration of these cells and showed antiangiogenic activity in HUVEC-2 cells at sublethal concentrations.

[31]

0.25-1 μg/ml

BEA caused mitochondrial dysfunction by affecting the mitochondrial volume regulation, oxidative phosphorylation and potassium ion homeostasis.

The cellular toxicity targets of BEA are the mitochondrion and the homeostasis of potassium ions.

[44]

10 μM

24 hours

BEA decreased the phosphorylation of ERK and strongly increases JNK phosphorylation; NK-κB activity was also inhibited.

BEA mediates its toxic effects in H4IIE cells, at least in parts, by a distinct modulation of intracellular signaling molecules.

[20]

24 hous

BEA induced apoptosis through decreasing of ROS generation, lossing of mitochondrial membrane potential, releasing of cyt c, and activation of caspase-9/3.

BEA exhibits anticancer activity against KB and KBv200 cell mainy due to the apoptosis via mitochondrial pathway.

[18]

24 hours

BEA induced the cell apoptosis and activated the pathway MEK1/2-ERK42/44-90RSK.

MEK1/2-ERK42/44-90RSK pathway plays an important role in BEA-induced apoptosis in human NSCLC A539 cancer cells.

[15]

24 hours

BEA suppressed NF-κB-dependent inflammatory responses by suppressing both Src and Syk.

BEA is a strong anti-inflammatory agent that attenuates NF-κB-dependent inflammatory responses by inhibiting both Src and Syk.

[13]

BEA inhibits proliferation and activation and induces apoptosis by targeting PI3K/AKT in activated T cells.

[21]

BEA is a promising novel natural compound for anticancer therapy.

[19]

1-10 μM

3-12 μM

1-10 μM

2 and 4 μM

1-4 mg/kg

7 days

BEA inhibited T cell activation and proliferation and induced apoptosis of activated lymphocytes. BEA inhibited PI3K/AKT pathway.

Mice bearing murine CT-26 or human KB-31-grafted tumors

5 mg/kg body weight

17 days

BEA decreased the tumor volumes and weights without any adverse effects in mice. Moderate BEA accumulation was detected in tumor tissues.

frequently detected mycotoxin and was present in 98% of the tested samples. BEA was also detected in maize feed samples from Iowa, USA [73]. A recent study revealed the presence of BEA and other structurally related mycotoxins in various species of Chinese medicinal herbs, with ginger having the highest BEA concentration [74]. Like trichothecenes, humans can be exposed to BEA through skin permeation [75]. The Panel of Contaminants in the Food Chain (CONTAM) of the European

Food Safety Authority has released a scientific opinion report on the potential toxicity of BEA for humans [76]. Considering all in vitro and the few in vivo studies, as well as the occurrence of BEA in different food products. CONTAM has concluded that acute exposure to BEA is not a concern for human health [76]. Unfortunately, studies of BEA toxicity in vivo are very limited and a better understanding of the long-term effect of BEA in the human diet is still necessary [77]. The most important contributors to chronic dietary ex-

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Fig. (2). Speculated mechanisms of the anticancer activity of beauvericin. Dotted arrows indicated the unclear specific mechanisms.

posure to BEA are grains and grain-based products, especially bread and rolls, fine bakery products and Pasta (raw). However, given the lack of relevant toxicity data, a risk assessment is still difficult [76, 78]. For other animals, the lack of LOAELs/NOAELs precludes the estimation of chronic health risk from BEA. CONCLUSION BEA is a bioactive compound of fungal origin that shows different kinds of bioactivities with a unique uncharacterized active mechanism. It could be a great discovery in pharmacology and toxicology. It has a therapeutic potential against deadly diseases such as cancer and viral or bacterial infections. On the other hand, BEA is produced by a number of filamentous fungi, which are a regular part of food and food ingredients as contaminants, and it is not yet clear whether long-term consumption of low doses of this mycotoxin poses a risk to human and animal health. Therefore, further studies must be undertaken in order to assess the usefulness of BEA

as a substance that usable in agriculture or medicine and also the risk of its presence in food for human and animal health. Based on the current data, BEA may be useful for the development of new chemical compounds in cancer therapy due to its relatively high toxicity and the induction of cancer cell apoptosis, as well as the regulation of a series of signalling pathways. However, as discussed before, there is a clear lack in the in vivo anticancer data concerning BEA and most of the current conclusions come from in vitro studies. Therefore, in the future, tests of the anticancer activity of BEA in animals are urgently needed. Moreover, the anticancer profiles of the BEA-mAb and the autophagy mechanism in this context should be studied. Finally, there is a need for further data on the co-occurrence of BEA with other Fusarium toxins in food and feed, as well as the possible combined effects. CONSENT FOR PUBLICATION Not applicable.

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CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

[19]

ACKNOWLEDGEMENTS This work was supported by the long-term organization development plan (UHK and UHHK) and the National Natural Science Foundation of China (grant no. 31602114). REFERENCES [1]

[2] [3]

[4]

[5]

[6]

[7] [8]

[9]

[10]

[11]

[12] [13]

[14]

[15]

[16]

[17]

[18]

Hamill, R.L.; Higgens, C.E.; Boaz, H.E.; Gorman, M. The structure op beauvericin, a new depsipeptide antibiotic toxic to Artemia salina. Tetrahedron Lett., 1969, 10(49), 4255-4258. Patocka, J. Bioactive metabolites of entomopathogenic fungi Beauveria bassiana. Mil. Med. Sci. Lett., 2016, 85(2), 80-88. Shivani, S.; Sardul, S.S.; Tapan, K.M. Pharmacological a therapeutic potential of beauvericin: a short review. J. Proteom. Bioinfrom., 2017, 10(1), 18-23. Fornelli, F.; Minervini, F.; Logrieco, A. Cytotoxicity of fungal metabolites to lepidopteran (Spodoptera frugiperda) cell line (SF9). J. Invertebrate Pathol., 2004, 85(2), 74-79. Jow, G.M.; Chou, C.J.; Chen, B.F.; Tsai, J.H. Beauvericin induces cytotoxic effects in human acute lymphoblastic leukemia cells through cytochrome c release, caspase 3 activation: The causative role of calcium. Cancer Lett., 2004, 216(2), 165-73. Leland, J.E.; McGuire, M.R.; Grace, J.A.; Jaronski, S.T.; Ulloa, M.; Park, Y.H.; Plattner, R.D. Strain selection of a fungal entomopathogen, Beauveria bassiana, for control of plant bugs (Lygus spp.) (Heteroptera: Miridae). Biol. Control, 2005, 35(2), 104-114. Cheng, C.K.; Chang, K.C.; Lee, Y.J. Antiproliferative effect of beauvericin on retinoblastoma. Fu-Jen. J. Med., 2009, 7(4), 161-169. Fu, M.; Li, R.; Guo, C.; Pang, M.; Liu, Y.; Dong, J. Natural incidence of Fusarium species and fumonisins B1 and B2 associated with maize kernels from nine provinces in China in 2012. Food Addit. Contaminants Part A, 2015, 32(4), 503-511. Svingen, T.; Lund Hansen, N.; Taxvig, C.; Vinggaard, A.M.; Jensen, U. Have Rasmussen P. Enniatin B and beauvericin are common in Danish cereals and show high hepatotoxicity on a highcontent imaging platform. Environ. Toxicol., 2017, 32(5), 16581664. Ferrer, E.; Juan-García, A.; Font, G.; Ruiz, M.J. Reactive oxygen species induced by beauvericin, patulin and zearalenone in CHOK1 cells. Toxicol. In Vitro, 2009, 23(8), 1504-1509. Feudjio, F.T.; Dornetshuber, R.; Lemmens, M.; Hoffmann, O.; Lemmens-Gruber, R.; Berger, W. Beauvericin and enniatin. emerging toxins and/or remedies? World Mycotoxin J., 2010, 3(4), 415430. Qadri, S.M.; Kucherenko, Y.; Lang, F. Beauvericin induced erythrocyte cell membrane scrambling. Toxicology, 2011, 283(1), 24-31. Yoo, S.; Kim, M.Y.; Cho, J.Y. Beauvericin, a cyclic peptide, inhibits inflammatory responses in macrophages by inhibiting the NFκB pathway. Korean J. Physiol. Pharmacol., 2017, 21(4), 449-456. Mallebrera, B.; Prosperini, A.; Font, G.; Ruiz, M.J. In vitro mechanisms of Beauvericin toxicity: A review. Food Chem. Toxicol., 2018, 111, 537-545. Lu, C.L.; Lin, H.I.; Chen, B.F.; Jow, G.M. Beauvericin-induced cell apoptosis through the mitogen-activated protein kinase pathway in human nonsmall cell lung cancer A549 cells. J. Toxicol. Sci., 2016, 41(3), 429-437. Lin, H.I.; Lee, Y.J.; Chen, B.F.; Tsai, M.C.; Lu, J.L.; Chou, C.J.; Jow, G.M. Involvement of Bcl-2 family, cytochrom c and caspase 3 in induction of apoptosis by beauvericin in human non-small cell lung cancer cells. Cancer Lett., 2005, 230, 248-259. Que, F.G.; Gores, G.J.; Larusso, N.F. Development and initial application of an in vitro model of apoptosis in rodent cholangiocytes. Am. J. Physiol., 1997, 35, 106-115. Tao, Y.W.; Lin, Y.C.; She, Z.G.; Lin, M.T.; Chen, P.X.; Zhang, J.Y. Anticancer activity and mechanism investigation of beauvericin isolated from secondary metabolites of the mangrove

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

endophytic fungi. Anticancer Agents Med. Chem., 2015, 15(2), 258-266. Heilos, D.; Rodríguez-Carrasco, Y.; Englinger, B.; Timelthaler, G.; van Schoonhoven, S.; Sulyok, M.; Boecker, S.; Süssmuth, R.D.; Heffeter, P.; Lemmens-Gruber, R.; Dornetshuber-Fleiss, R.; Berger, W. The natural fungal metabolite beauvericin exerts anticancer activity in vivo: A pre-clinical pilot study. Toxins (Basel)., 2017, 9(9), E258. Wätjen, W.; Debbab, A.; Hohlfeld, A.; Chovolou, Y.; Proksch, P. The mycotoxin beauvericin induces apoptotic cell death in H4IIE hepatoma cells accompanied by an inhibition of NF-κB-activity and modulation of MAP-kinases. Toxicol. Lett., 2014, 231(1), 9-16. Wu, X.F.; Xu, R.; Ouyang, Z.J.; Qian, C.; Shen, Y.; Wu, X.D.; Gu, Y.H.; Xu, Q.; Sun, Y. Beauvericin ameliorates experimental colitis by inhibiting activated T cells via downregulation of the PI3K/Akt signaling pathway. PLoS One, 2013, 8(12), e83013. Massini, P.; Näf, U. Ca2+ ionophores and the activation of human blood platelets. The effects of ionomycin, beauvericin, lysocellin, virginiamycin S, lasalocid-derivatives and McN 4308. Biochimica. Et. Biophysica. Acta., 1980, 598(3), 575. Tang, Y.; Li, J.; Li, F.; Hu, C.A.; Liao, P.; Tan, K.; Tan, B.; Xiong, X.; Liu, G.; Li, T.; Yin, Y. Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway. Free Radic. Biol. Med., 2015, 89, 944951. Campos, F.F.; Sales Junior, P.A.; Romanha, A.J.; Araújo, M.S.; Siqueira, E.P.; Resende, J.M.; Alves, T.M.; Martins-Filho, O.A.; Santos, V.L.; Rosa, C.A.; Zani, C.L.; Cota, B.B. Bioactive endophytic fungi isolated from Caesalpinia echinata Lam. (Brazilwood) and identification of beauvericin as a trypanocidal metabolite from Fusarium sp. Mem. Inst. Oswaldo. Cruz., 2015, 110(1), 65-74. Mogensen, J.M.; Sørensen, S.M.; Sulyok, M.; van der Westhuizen, L.; Shephard, G.S.; Frisvad, J.C.; Thrane, U.; Krska, R.; Nielsen, K.F. Single-kernel analysis of fumonisins and other fungal metabolites in maize from South African subsistence farmers. Food Addit. Contam. Part A, 2011, 28(12), 1724-1734. Wang, J.; Zhang, D.M.; Jia, J.F.; Peng, Q.L.; Tian, H.Y.; Wang, L.; Ye, W.C. Cyclodepsipeptides from the ascocarps and insect-body portions of fungus Cordyceps cicadae. Fitoterapia, 2014, 97, 2327. Luangsa-Ard, J.J.; Berkaew, P.; Ridkaew, R.; Hywel-Jones, N.L.; Isaka, M. A beauvericin hot spot in the genus Isaria. Mycol. Res., 2009, 113(12), 1389-1395. Stanciu, O.; Juan, C.; Miere, D.; Loghin, F.; Mañes, J. Presence of enniatins and beauvericin in Romanian wheat samples: From raw material to products for direct human consumption. Toxins (Basel), 2017, 9(6), E189. Xu, L.; Wang, J.; Zhao, J.; Li, P.; Shan, T.; Wang, J.; Li, X.; Zhou, L. Beauvericin from the endophytic fungus, Fusarium redolens, isolated from Dioscorea zingiberensis and its antibacterial activity. Nat. Prod. Commun., 2010, 5(5), 811-814. Xu, L.J.; Liu, Y.S.; Zhou, L.G.; Wu, J.Y. Modeling of Fusarium redolens Dzf2 mycelial growth kinetics and optimal fed-batch fermentation for beauvericin production. J. Industr. Microbiol. Biotechnol., 2011, 38(9), 1187-1192. Zhan, J.; Burns, A.M.,;Liu, M.X.,;Faeth, S.H.; Gunatilaka, A.A.L. Search for cell motility and angiogenesis inhibitors with potential anticancer activity: Beauvericin and other constituents of two endophytic strains of Fusarium oxysporum. J. Nat. Prod., 2007, 70, 227-232. Spencer, N.J. Motility patterns in mouse colon: gastrointestinal dysfunction induced by anticancer chemotherapy. Neurogastroenterol Motil., 2016, 8(12), 1759-1764. Anasamy, T.; Thy, C.K.; Lo, K.M.; Chee, C.F.; Yeap, S.K.; Kamalidehghan, B.; Chung, L.Y. Tribenzyltin carboxylates as anticancer drug candidates: Effect on the cytotoxicity, motility and invasiveness of breast cancer cell lines. Eur. J. Med. Chem., 2017, 125, 770-783. Tolleson, W.H.; Melchior, W.B.J.; Morris, S.M.; McGarrity, L.J.; Domom, O.E. Apoptosis and antiproliferative effects of fumonisin B1 in human keratinocytes, fibroblasts, esophageal epithelial cells, and hepatom cells. Carcinogenesis, 1996, 17, 239.

Beauvericin, A Fusarium Mycotoxin: Anticancer Activity

Mini-Reviews in Medicinal Chemistry, 2019, Vol. 19, No. 3

[35]

endoplasmic reticulum Ca2+: a control point for apoptosis. Science, 2003, 300(5616), 135-139. Ruan, H.B.; Ma, Y.; Torres, S.; Zhang, B.; Feriod, C.; Heck, R.M.; Qian, K.; Fu, M.; Li, X.; Nathanson, M.H.; Bennett, A.M.,;Nie, Y.; Ehrlich, B.E.; Yang, X. Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes Dev., 2017, 31(16), 1655-1665. Huang, Q.; Cao, H.; Zhan, L.; Sun, X.; Wang, G.; Li, J.; Guo, X.; Ren, T.T.; Wang, Z.; Lyu, Y.H. Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Cancer Lett., 2017, 403, 108. Ojcius, D.M.; Zychlinsky, A.; Zheng, L.M.; Young, J.D. Ionophore-induced apoptosis: role of DNA fragmentation and calcium fluxes. Exp. Cell Res., 1991, 197, 43-49. Kim, M.K.; Seong, S.Y.; Seoh, J.Y.; Han, T.H.; Song, H.J.; Lee, J.E.; Shin, J.H.; Lim, B.U.; Kang, J.S. Orientia tsutsugamushi inhibits apoptosis of macrophages by retarding intracellular calcium release. Infect. Immun., 2002, 70, 4692-4696. Bieber, K.; Koga, H.; Nishie, W. In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases. Exp. Dermatol., 2017, 26(12), 1163-1170. Nesslany, F. The current limitations of in vitro genotoxicity testing and their relevance to the in vivo situation. Food Chem. Toxicol., 2017, 106(Pt B), 609-615. Antignani, A.; FitzGerald, D. Immunotoxins: the role of the toxin. Toxins, 2013, 5(8), 1486-1502. Weidle, U.H.; Tiefenthaler, G.; Schiller, C.; Weiss, E.H.; Georges, G.; Brinkmann, U. Prospects of bacterial and plant protein-based immunotoxins for treatment of cancer. Cancer Genom. Proteom., 2014, 11(1), 25-38. Allahyari, H.; Heidari, S.; Ghamgosha, M.; Saffarian, P.; Amani, J. Immunotoxin: A new tool for cancer therapy. Tumour Biol., 2017, 39(2), 1010428317692226. Ohtani, K.; Murakami, H.; Shibuya, O.; Kawamura, O.; Ohi, K.; Chiba, J.; Otokawa, M.; Ueno, Y. Antitumor activity of T-2 toxinconjugated monoclonal antibody to murine thymoma. Jpn. J. Exp. Med., 1990, 60(2), 57-65. Kojima, S.; Nakamura, N.; Ueno, Y.; Yamaguchi, T.; Takahashi, T. Anti-tumor activity of T-2 toxin-conjugated A7 monoclonal antibody (T-2-A7 MoAb) against human colon carcinoma. Nat. Toxins., 1993, 1(4), 209-215. Nagar, R. Autophagy: A brief overview in perspective of dermatology. Indian J. Dermatol. Venereol. Leprol., 2017, 83(3), 290–297. Reyes-Velázquez, W.P.; Figueroa-Gómez, R.M.; Barberis, M.; Reynoso, M.M.; Rojo, F.G.; Chulze, S.N.; Torres, A.M. Fusarium species (section Liseola) occurrence and natural incidence of beauvericin, fusaproliferin and fumonisins in maize hybrids harvested in Mexico. Mycotoxin Res., 2011, 27(3), 187-194. Jestoi, M. Emerging Fusarium - Mycotoxins Fusaproliferin, Beauvericin, Enniatins, and Moniliformin—A Review. Crit. Rev. Food Sci. Nutr., 2008, 48(1), 21-49. Jestoi, M.; Rokka, M.; Yli-Mattila, T.; Parikka, P.; Rizzo, A.; Peltonen, K. Presence and concentrations of the Fusarium-related mycotoxins beauvericin, enniatins and moniliformin in finnish grain samples. Food Addit. Contam., 2004, 21(8), 794–802. Moretti, A.; Logrieco, A.; Bottalico, A.; Ritieni, A.; Randazzo, G. Production of beauvericin by Fusarium proliferatum from maize in Italy. Mycotoxin Res., 1994, 10(2), 73-78. Bottalico, A.; Logrieco, A.; Ritieni, A.; Moretti, A.; Randazzo, G.; Corda, P. Beauvericin and fumonisin B1 in preharvest Fusarium moniliforme maize ear rot in Sardinia. Food Addit. Contam., 1995, 12(4), 599-607. Moretti, A.; Mulé, G.; Ritieni, A.; Láday, M.; Stubnya, V.; Hornok, L.; Logrieco, A. Cryptic subspecies and beauvericin production by Fusarium subglutinans from Europe. Int. J. Food Microbiol., 2008, 127(3), 312-315. Sifou, A.; Meca, G.; Serrano, A.B.; Mahnine, N.; Abidi, A.E.; Mañes, J.; El Azzouzi, M.E.; Abdellah Zinedine, A. First report on the presence of emerging Fusarium mycotoxins enniatins (A, A1, B, B1), beauvericin and fusaproliferin in rice on the Moroccan retail markets. Food Control, 2011, 22, 1826-1830.

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

Kegvi, T.; Klarit, M.; Pepeljnjak, S.; Domijan, A.M.; Petrik, J. Lipid peroxidation and glutathione levels in porcine kidney PK15 cells after indiividual and combined treatment with fumonisin B1, beauvericin and ochratoxinn A. Basic Clin. Pharmacol. Toxicol., 2007, 100(3), 157-164. Dombrink-Kurtzman, M.A. Fumonisin and beauvericin induce apoptosis in turkey peripheral blood lymphocytes. Mycopathologia, 2003, 156(4), 357-364. Klarić, M.S.; Rumora, L.; Ljubanović, D.; Pepeljnjak, S. Cytotoxicity and apoptosis induced by fumonisin B(1), beauvericin and ochratoxin A in porcine kidney PK15 cells: effects of individual and combined treatment. Arch. Toxicol., 2008, 82(4), 247-255. Tang, C.Y.; Chen, Y.W.; Jow, G.M.; Chou, C.J.; Jeng, C.J. Beauvericin activates Ca2+-activated Cl- currents and induces cell deaths in Xenopus oocytes via influx of extracellular Ca2+. Chem. Res. Toxicol., 2005, 18(5), 825-33. Chen, B.F.; Tsai, M.C.; Jow, G.M. Induction of calcium influx from extracellular fluid by beauvericin in human leukemia cells. Biochem. Biophys. Res. Commun., 2006, 340(1), 134-139. Niazi, M.; Zakeri-Milani, P.; Najafi Hajivar, S.; Soleymani Goloujeh, M.; Ghobakhlou, N.; Shahbazi Mojarrad, J.; Valizadeh, H. Nano-based strategies to overcome p-glycoprotein-mediated drug resistance. Expert Opin. Drug Metab. Toxicol., 2016, 12(9), 10211033. Ansari, S.M.; Saquib, Q.; Attia, S.M.; Abdel-Salam, E.M.; Alwathnani, H.A.; Faisal, M.; Alatar, A.A.; Al-Khedhairy, A.A.; Musarrat, J. Pendimethalin induces oxidative stress, DNA damage, and mitochondrial dysfunction to trigger apoptosis in human lymphocytes and rat bone-marrow cells. Histochem. Cell Biol., 2018, 149(2), 127-141. Wu, Q.; Wang, X.; Wan, D.; Li, J.; Yuan, Z. Crosstalk of JNK1STAT3 is critical for RAW264.7 cell survival. Cell. Signal., 2014, 26(12), 2951-2960. Wu, Q.H.; Wang, X.; Yang, W.; Nüssler, A.K.; Xiong, L.Y.; Kuča, K.; Dohnal, V.; Zhang, X.J.; Yuan, Z.H. Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update. Arch. Toxicol., 2014, 88(7), 13091326. Tonshin, A.A.; Teplova, V.V.; Andersson, M.A.; SalkinojaSalonen, M.S. The Fusarium mycotoxins enniatins and beauvericin cause mitochondrial dysfunction by affecting the mitochondrial volume regulation, oxidative phosphorylation and ion homeostasis. Toxicology, 2010, 276(1), 49-57. Klarić, M.S.; Pepeljnjak, S.; Domijan, A.M.; Petrik, J. Lipid peroxidation and glutathione levels in porcine kidney PK15 cells after individual and combined treatment with fumonisin B(1), beauvericin and ochratoxin A. Basic Clin. Pharmacol. Toxicol., 2007, 100(3), 157-164. Prosperini, A.; Juan-García, A.; Font, G.; Ruiz, M.J. Beauvericininduced cytotoxicity via ROS production and mitochondrial damage in Caco-2 cells. Toxicol. Lett., 2013, 222(2), 204-211. Wu, Q.; Wang, X.; Nepovimova, E.; Miron, A.; Liu, Q.; Wang, Y.; Su, D.; Yang, H.; Li, L.; Kuca, K. Trichothecenes: immunomodulatory effects, mechanisms, and anti-cancer potential. Arch. Toxicol., 2017, 91(12), 3737-3785. Wu, Q.; Wang, X.; Nepovimova, E.; Wang, Y.; Yang, H.; Li, L.; Zhang, X.; Kuca, K. Antioxidant agents against trichothecenes: new hints for oxidative stress treatment. Oncotarget, 2017, 8(66), 110708-11072. Dornetshuber, R.; Heffeter, P.; Lemmens-Gruber, R.; Elbling, L.; Marko, D.; Micksche, M.; Berger, W. Oxidative stress and DNA interactions are not involved in Enniatin- and Beauvericinmediated apoptosis induction. Mol. Nutr. Food Res., 2009, 53(9), 1112-1122. Wu, Y.J.; Tang, L. Bcl-2 family proteins regulate apoptosis and epithelial to mesenchymal transition by calcium signals. Curr. Pharm. Des., 2016, 22(30), 4700-4704. Zhou, X.; Hao, W.; Shi, H.; Hou, Y.; Xu, Q. Calcium homeostasis disruption - a bridge connecting cadmium-induced apoptosis, autophagy and tumorigenesis. Oncol. Res. Treat., 2015, 38(6), 311-315. Scorrano, L.; Oskes, S.A.; Opferman, J.T.; Cheng, E.H.; Sorcinelli, M.D.; Pozzan, T.; Korsmeyer, S.J. BAX and BAK regulation of

[53]

[54]

[55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64] [65]

[66]

[67]

[68]

[69]

[70]

[71]

213

214 [72]

[73]

[74]

[75]

Mini-Reviews in Medicinal Chemistry, 2019, Vol. 19, No. 3

Wu et al.

Streit, E.; Schwab, C.; Sulyok, M.; Naehrer, K.; Krska, R.; Schatzmayr, G. Multi-mycotoxin screening reveals the occurrence of 139 different secondary metabolites in feed and feed ingredients. Toxins, 2013, 5(3), 504-523. Munkvold, G.; Stahr, H.M.; Logrieco, A.; Moretti, A.; Ritieni, A. Occurrence of fusaproliferin and beauvericin in Fusariumcontaminated livestock feed in Iowa. Appl. Environ. Microbiol., 1998, 64(10), 3923-3926. Hu, L.; Rychlik, M. Occurrence of enniatins and beauvericin in 60 Chinese medicinal herbs. Food Addit. Contam. Chem. Anal. Control Expo. Risk Assess., 2014, 31(7), 1240-1245. Taevernier, L.; Veryser, L.; Roche, N.; Peremans, K.; Burvenich, C.; Delesalle, C.; De Spiegeleer, B. Human skin permeation of

[76]

[77]

[78]

emerging mycotoxins (beauvericin and enniatins). J. Expo. Sci. Environ. Epidemiol., 2016, 26(3), 277-287. EFSA. Scientific opinion on the risks to human and animal health related to the presence of beauvericin and enniatins in food and feed. EFSA Panel on Contaminants in the Food Chain. EFSA J., 2014, 12(174), 2902. Luz, C.; Saladino, F.; Luciano, F.B.; Mañes, J.; Meca, G. Occurrence, toxicity, bioaccessibility and mitigation strategies of beauvericin, a minor Fusarium mycotoxin. Food Chem. Toxicol., 2017, 107(Pt A), 430-439. Wang, Q.; Xu, L. Beauvericin, a bioactive compound produced by fungi: A short review. Molecules, 2012, 17(3), 2367-2377.

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PMID: 30264680