Plant Coumestans: Recent Advances and Future Perspectives in Cancer Therapy
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Send Orders for Reprints to [email protected] Anti-Cancer Agents in Medicinal Chemistry, 2014, 14, 000-000 1 Plant Coumestans: Recent Advances and Future Perspectives in Cancer Therapy Tereza Nehybová1, Jan Šmarda1 and Petr Beneš1,2,* 1Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic and Masaryk Memorial Cancer Institute, RECAMO, Žlutý kopec 7, 656 53 Brno, Czech Republic; 2International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Brno, Czech Republic Abstract: Natural products are often used in drug development due to their ability to form unique and diverse chemical structures. Coumestans are polycyclic aromatic plant secondary metabolites containing a coumestan moiety, which consists of a benzoxole fused to a chromen-2-one to form 1-Benzoxolo[3,2-c]chromen-6-one. These natural compounds are known for large number of biological activities. Many of their biological effects can be attributed to their action as phytoestrogens and polyphenols. In the last decade, anticancer effects of these compounds have been described in vitro but there is only limited number of studies based on models in vivo. More information concerning their in vivo bioavailability, stability, metabolism, toxicity, estrogenicity, cellular targets and drug interactions is therefore needed to proceed further to clinical studies. This review focuses on coumestans exhibiting anticancer properties and summarizes mechanisms of their toxicity to cancer cells. Moreover, the possible role of coumestans in cancer prevention is discussed. Keywords: Cancer, cellular target, coumestrol, coumestan, glycyrol, psoralidin, therapy, wedelolactone. INTRODUCTION also acts as antioxidant [18, 36] and prevents bone resorption by Natural products are often used in drug development due to inhibiting differentiation and function of osteoclasts and by their ability to form unique and diverse chemical structures. Natural supporting proliferation, differentiation and function of osteoblasts compounds and their derivatives are commonly used for prevention [37-42]. In addition, it inhibits adipocyte differentiation and lipogenesis and treatment of various diseases, including cancer. Interestingly, [43, 44], affects insulin sensitivity, lipid and glucose metabolism half of the small molecules approved by U.S. Food and Drug [45-48], antagonizes pregnane X receptor (PXR) [49, 50], inhibits Administration (FDA) agency in 2010 were natural products or aryl hydrocarbon receptor (AhR) activation by environmental their derivatives, including majority of the antitumor agents. This contaminants [51], and regulates steroid metabolism by inhibiting suggests that natural products represent an important source of aromatase and 17β-hydroxysteroid dehydrogenase [52-54]. Coumestrol anticancer drugs [1, 2]. Many anticancer drugs that are currently in was also shown to be involved in epigenetic control of gene clinical use, including some of the best known as vinblastine, expression by deregulating methylation of specific genes in female vincristine, paclitaxel, camptothecin are derived from plants [1]. rat pancreas [55]. Coumestans are polycyclic aromatic plant secondary metabolites Many of the coumestrol effects mentioned above are mediated containing a coumestan moiety. These compounds were identified by estrogen receptors (ERs). Numerous studies demonstrated that and isolated from variety of plants and exhibit hepatoprotective, coumestrol is a phytoestrogen acting as agonist of both ERα and antimyotoxic, antifibrotic, antiinflammatory, antiproteolytic, ERβ with stronger binding affinity to ERβ [19, 56, 57]. The antihemorrhagic, neuroprotective, estrogenic, antimicrobial, coumestrol binding affinity to ERα is weaker in comparison to antifungal, antihelmintic, antioxidative and immunomodulatory endogenous 17β-estradiol (E2) [19, 58]. On the other hand, binding properties [3-19]. The plant-derived coumestan family of compounds affinity of these two compounds to ERβ is similar [19, 59]. The includes coumestrol, wedelolactone, demethylwedelolactone, effects of ERα and ERβ on tumor growth, metastases and chemo- psoralidin, flemicoumestan A 1, glycyrol, erythribyssin N, aureol, sensitivity are different reflecting regulation of various genes by tephcalostan, plicadin, sophoracoumestan A, coumestoside C, D, binding to distinct regulatory elements recruiting distinct coregulators hedysarimcoumestans A, B, D, F and many others [11, 13, 20-29]. and chromatin remodelling factors. Several findings, reviewed by Moreover, other coumestan derivatives were synthesized to Leitman et al. and Burns et al., demonstrated that expression/ improve their antiviral and antimyotoxic properties [30-32]. In this activation of ERβ can modulate or even oppose pro-proliferative review, we focus on coumestrol, wedelolactone, psoralidin and effects of ERα [60, 61]. The anti-proliferative and anti-metastatic glycyrol – the coumestans with anticancer effects. Molecular effects of phytoestrogens may be therefore explained by their mechanisms mediating their effects on cancer cells are summarized higher affinity to ERβ compared to ERα [61-63]. (Fig. 1) and discussed. Both genomic and nongenomic mechanisms have been proposed to mediate phytoestrogenic effects of coumestrol (Fig. 3). COUMESTROL Coumestrol binds to nuclear ERs and induces expression of specific Coumestrol (Fig. 2) was originally isolated from alfalfa [20]. estrogen-responsive genes that regulates various cellular processes, Subsequently, this plant coumestan was found in a variety of such as growth and survival [63, 64]. A strong correlation between legumes, soybeans, brussels sprouts, clover and spinach. Coumestrol expression profiles induced by coumestrol and E2 in ERα- was demonstrated to posses a wide range of biological effects including expressing cancer cells was reported but was less obvious in the neuroprotection [33, 34] and immunomodulation [16, 17, 35]. It presence of ERβ, suggesting that activation of ERβ by coumestrol can modulate its ERα-stimulating effects in cells [63]. Coumestrol can also initiate signaling from the membrane ERs by activation of *Address correspondence to this author at the Department of Experimental 2+ Biology, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, ERK1/2, JNK, PI3K, Syc and changes in Ca fluxes [65-70]. Czech Republic; Tel: +420 54949 3125; Fax: +420 54949 5533; Phytoestrogens often exert biphasic effect on the ER-responsive E-mail: [email protected] cancer cells [71]. Coumestrol in doses lower than 10-7 M enhances 1871-5206/14 $58.00+.00 © 2014 Bentham Science Publishers 2 Anti-Cancer Agents in Medicinal Chemistry, 2014, Vol. 14, No. 0 Nehybová et al. Fig. (1). Cancer-related activities of coumestans. Fig. (2). Chemical structures of coumestans with anticancer properties. proliferation of breast and pituitary cancer cells by stimulation of As phytoestrogens directly interacts with ERs, it has been the G1/S cell cycle transition, cyclin D1 over-expression along with suggested that they can block binding of endogenous estrogen and ERK 1/2 and JNK phosphorylation. These effects are inhibited by thus act as estrogen antagonists. This antagonism in binding to ERs the ER antagonist ICI 182,780 [69, 72-74]. At higher doses, was suggested for coumestrol as well [56, 57, 80]. However, however, coumestrol induces apoptosis/cell death of breast, coumestrol did not inhibit the E2-mediated gene transactivation pancreatic, ovarian, and prostate cancer cells. The induction of from ERE (estrogen responsive element) and the E2-induced apoptosis by coumestrol is associated with caspase activation and proliferation of breast cancer and HeLa cells [71, 80, 81]. downregulation of antiapoptotic Bcl-2 protein [35, 65, 66, 72, 75, Moreover, in some of these studies, additive effects of both 76, 77-79]. compounds were reported [82, 83]. Interestingly, coumestrol at very Coumestans in Cancer Prevention and Treatment Anti-Cancer Agents in Medicinal Chemistry, 2014, Vol. 14, No. 0 3 Fig. (3). Genomic and nongenomic effects of coumestrol in estrogen signaling. low doses attenuated the proliferative effects of E2 in rat pituitary through down-regulation of the CKII-specific Akt phosphorylation. cells [69]. These contradictory results may reflect differences in Furthermore, coumestrol-induced senescence of breast cancer doses of coumestrol and estrogens, cell and tissue specificity, the MCF-7 and colon cancer HCT116 cells was antagonized by type of reporter assays, the presence/absence/activity of ER- overexpression of CKII [91]. Inhibition of CKII by coumestrol coactivators, the ratio of ERα/ERβ or may also reflect multiple resulted in activation of NADPH oxidase, reactive oxygen species mechanisms of action of coumestrol in cells. Numerous studies (ROS) production and activation of the p53-p21 (Cip1/WAF1) reported that coumestrol acts as phytoestrogen and endocrine pathway resulting in cellular senescence [92]. disrupter in vivo by affecting several endocrine mechanisms during Coumestrol interacts with DNA [101] and posses mutagenic the estrous cycle resulting in abnormalities in the development of and clastogenic properties. It induces mutations in TA97 and male and female reproductive tracts and infertility. Pathologies, TA102 strains of Salmonella typhimurium [102] as well as DNA such as lack of ovulations, cervical and uterine lesions and strand breaks, chromosomal aberrations, micronuclei and somatic paraovarian