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Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive Mechanisms a

a

Kyung-A Hwang & Kyung-Chul Choi a

Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea Published online: 21 May 2015.

Click for updates To cite this article: Kyung-A Hwang & Kyung-Chul Choi (2015): Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive Mechanisms, Nutrition and Cancer, DOI: 10.1080/01635581.2015.1040516 To link to this article: http://dx.doi.org/10.1080/01635581.2015.1040516

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Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive Mechanisms Kyung-A Hwang and Kyung-Chul Choi

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Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea

Phytoestrogens are phenolic compounds derived from plants and exert an estrogenic as well as an antiestrogenic effect and also various biological efficacies. Chemopreventive properties of phytoestrogens has emerged from epidemiological observations indicating that the incidence of some cancers including breast and prostate cancers is much lower in Asian people, who consume significantly higher amounts of phytoestrogens than Western people. There are 4 main classes of phytoestrogens: isoflavones, stilbenes, coumestans, and lignans. Currently, resveratrol is recognized as another major phytoestrogen present in grape and red wine and has been studied in many biological studies. Phytoestrogens have biologically diverse profitabilities and advantages such as low cytotoxicity to patients, lack of side effects in clinical trials, and pronounced benefits in a combined therapy. In this review, we highlighted the effects of genistein, daidzein, and resveratrol in relation with their anticarcinogenic activity. A lot of in vitro and in vivo results on their chemopreventive properties were presented along with the underlying mechanisms. Besides well-known mechanisms such as antioxidant property and apoptosis, newly elucidated anticarcinogenic modes of action including epigenetic modifications and topoisomerase inhibition have been provided to examine the possibility of phytoestrogens as promising reagents for cancer chemoprevention and/or treatment and to suggest the importance of plant-based diet of phytoestrogens.

INTRODUCTION Phytoestrogens are a class of biologically active phenolic compounds derived from plants and have structures that are similar to the principal mammalian estrogen, 17b-estradiol (E2) (1). They exert an estrogenic as well as an antiestrogenic effect and also various biological efficacies such as antioxidant property and chemoprevention against cancers. Especially, the importance of phytoestrogens in chemopreventive properties Submitted 17 February 2014; accepted in final form 9 April 2015. Address correspondence to Kyung-Chul Choi, Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea. Phone: +82-43-261-3664. Fax: +82-43-267-3150. E-mail: [email protected]

has emerged from epidemiological observations, indicating that the incidence of some cancers including breast and prostate cancers is much lower in Asian people, who consume significantly higher amounts of phytoestrogens than Westerners (2). According to the reports, Asian women have a threefold lower breast cancer risk than women in the United States (3). Also, the incidence and mortality of prostate cancer shows the highest rates in Western countries and the lowest rates in Asian countries (4). With respect to the diet of phytoestrogens, there are considerable differences between the amounts of phytoestrogen intake of people in 2 parts of area. The average daily intake of phytoestrogens of Asian population is estimated to be between 20 and 50 mg. In contrast, the average daily consumption of phytoestrogens in the United States and Europe is measured to be 0.15~3 mg and 0.49~1 mg, respectively (1,5). These results are thought to be related with traditional dietary habits; plant-based diet of Asian population and meat-based diet of Western population. In fact, phytoestrogens are the most prevalent compounds found in ordinary edible plants such as vegetables, fruits, legumes, and teas (6). Therefore, they are commonly ingested in Asian populations from daily diets without going through special process, which is one of the most profitable aspects in the availability of phytoestrogens. There are 4 main classes of phytoestrogens: isoflavones, stilbenes, coumestans, and lignans (1,6). Among these classes, isoflavones and lignans are more intensely studied than the other 2 classes (7). Isoflavones are mainly present in legumes such as soybean, kala channa, mung bean, red lentils, and red clover. Genistein and daidzein are the 2 major isoflavones found in soy beans (7). The dietary sources of lignans are flaxseed, sea weed, whole grains, oil seeds, fruits, and vegetables. Secoisolariciresinol diglucoside and matairesinol are the 2 major lignans (7). Besides, resveratrol is currently recognized as a major phytoestrogen present in grape and red wine and has been intensely studied for its effectiveness. In this review, we highlight the effects and underlying mechanisms of important phytoestrogens such as genistein, daidzein, and resveratrol in relation with their anticarcinogenic activity, because these 2 1

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K-A. HWANG AND K-C. CHOI

isoflavones and resveratrol are the most actively studied phytoestrogens in this field (8). Low cytotoxicity to patients, lack of side effects in clinical trials, and pronounced benefits in combined therapy with other treatments have activated the research for anticarcinogenic effects of phytoestrogens (7). Especially, the role of phytoestrogens in combined therapy was magnified in many other studies due to their adjuvant interactions with hormonal therapies using selective estrogen receptor modulators and aromatase inhibitors (9–13). For example, equol enhanced the anticancer activity of tamoxifen, an antagonist of estrogen receptor (ER), in estrogen dependent MCF-7 breast cancer cells, and a diet supplemented with soybean seeds synergistically increased tamoxifen’s suppressive effect in rat mammary tumor models (10,13). In addition, in the clinical trials on women with breast cancer, soy food consumption along with tamoxifen use was significantly associated with the decreased risk of death and recurrence (14), and high dietary intake of soy isoflavones was also correlated with lower risk of recurrence in those receiving anastrozole as endocrine therapy (15). However, these secondary preventive effects of phytoestrogens in combined therapies were not included in this review for illuminating the sole effect of each phytoestrogen. Overall, this review is aimed to examine the possiblility of genistein, daidzein, and resveratrol as natural food derived reagents for cancer chemoprevention and/or treatment by providing diverse anticancer efficacies and relevant mechanisms including newly elucidated ones and to suggest the importance of plant-based diet including phytoestrogens.

GENISTEIN Isoflavonoids are in a subclass of flavonoids, which are ketone or nonketone polyhydroxy polyphenol compounds as plant secondary metabolites, and fulfill many functions such as plant pigmentation, UV filtration and symbiotic nitrogen fixation. Genistein and daidzein are the mostly studied isoflavonoids derived from legumes. First, genistein, 40 ,5,7-trihydroxyisoflavone, is the predominant isoflavone in human diet, because it is mainly included in soybeans, peas, lentils and other beans (16). As a phytoestrogen, genistein has a potency of E2 by interacting with 2 isoforms of ERs: ERa and ERb. Genistein was shown to more closely interact with ERb than ERa from a luciferase reporter gene assay, showing that it has one-third the potency of E2 when it interacts with ERb and one-thousandth of the potency of E2 when it interacts with ERa (17). This higher binding affinity for ERb of genistein has been related with its action as an estrogen antagonist and chemopreventive activity. A higher binding affinity for ERb and ERb-mediated inhibition of ERa signaling pathway are associated with antiproliferative and antitumor properties, and a large series of phytoestrogens including genistein was investigated to have this tendency (18). The antiproliferative effect of genistein

was identified in the experiments with Sprague-Dawley rats, in which neonatal prepubertal exposure of E2 increased the number of terminal end buds and cell proliferation in mammary tissue; however, genistein reduced the number of terminal end buds and cell proliferation (19,20). We also have proven the antitumor effect of genistein in the recent studies. In BG-1 ovarian cancer cell line, E2 and bisphenol A (BPA), a typical endocrine disrupting chemical (EDC), identically increased the cell proliferation (21). On the other hand, the additional introduction of genistein significantly reduced the cell proliferation induced by E2 or BPA at 5.0 £ 10¡5 M and 2.5 £ 10¡5 M, respectively (21). This phenomenon was identified in the mouse xenograft model previously transplanted with BG-1 cell line. The cancer burden of E2 or BPA-administrated mice increased; however, when genistein was cotreated with E2 or BPA, the tumor volume was evidently reduced (22). From these results, genistein was confirmed to have a chemopreventive activity by abolishing the tumor progressive risk caused by E2 and BPA in ER-dependent BG-1 ovarian cancer. Genistein, furthermore, showed an anticarcinogenic effect on other cancers. It significantly inhibited the cell growth of human bladder cancer cell line 253 JB-V (23) and human renal carcinoma cell lines SMKT R-1, R-2, R-3, and R4 (24). In animal cancer models, genistein (15 mg/kg/day) or soybean-based diet reduced tumor cell migration of B16FO melanoma cells and angiogenesis in Balb/c mice (25). In addition, dietary soy at 10% and 20% (w/w) significantly was demonstrated to reduce the lung invasiveness of MDA-MB-435 human breast cancer cells (26). In another in vivo study using SD rats, dietary genistein (250 mg/kg diet) showed the protective effect against mammary and prostate cancers by regulating specific sex steroid receptors and growth factor signaling pathways (27). Anticarcinogenic mechanisms of genistein have been explained by its action on several biochemical targets. First, genistein is a potent inhibitor of protein tyrosine kinase (PTK), especially that of the epidermal growth factor receptor (EGFR) (28). Generally, PTKs play a central role in the control of cellular proliferation by transmitting mitogenic signals and its inactivation might be applied in the discovery of new anticancer compounds (29). Through dissecting signal transduction pathways of PTK, genistein can inhibit the growth of a wide variety of tumor cell types. For instance, EGF mediated growth stimulation of AGS gastric cancer cells was dosedependently reversed by co-incubation with genistein (30). Genistein also exerted multiple suppressive effects on the proliferation of ER-positive breast carcinoma cell lines by inhibiting estrogen-induced PTK activity (31). Second, the inhibition of topoisomerase II (Topo II), an important protein involved in the processes of DNA replication and cell proliferation and ribosomal S6 kinase (RS6K) activities, is associated with antiproliferative efficacy of genistein (32). Genistein inhibits Topo II and RS6K by stabilizing a cleavable Topo–DNA complex and modulating mRNA translation in vitro (33–35).

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ANTIPROLIFERATIVE EFFECT OF PHYTOESTROGENS ON CANCERS

Stabilization of this complex may lead to protein-linked DNA strand breaks, cell growth suppression, and differentiation induction of several malignant cell lines (36). A recent study indicates that genistein may be an anticancer food component because it prevented the proliferation of HCT116 human colon carcinoma cells and halted the cell cycle in G2/M phase by inhibiting cellular Topo II, not Topo I, and DNA polymerases (37). Genistein has a potent capability to decrease the production of reactive oxygen species (ROS) by tumor cell types and cells of the immune system (28). Because the production of ROS, especially by activated cells of the immune system, has been postulated to play a role in tumor promotion, the ROS scavenging or antioxidant effect of genistein might be related with anticarcinogenesis. For example, in LNCaP and PC-3 prostate cancer cell lines, the antioxidant effect of genistein prevented cancer progression, metastasis, and invasion (38). Genistein has been shown to inhibit both the priming events necessary for high level ROS production and agonist-stimulated ROS production (39–41). In addition, recent studies also show that genistein can contribute to cancer prevention as an epigenome modifier (42). At the epigenetic level, DNA methylation is thought to inhibit transcription of genes by regulating alterations in chromatin structure, and its patterns have been used as a marker for the study of cancer-related epigenetics (42,43). In animal experiments, genistein was positively correlated with changes in prostate DNA methylation at CpG islands of specific mouse genes. Thus, genistein, may be involved in preventing the development of certain prostate and mammary cancers by maintaining a protective DNA methylation profile (44). From another epigenetic point of view, genistein was shown to increase histone acetylation, which is responsible for a loosened chromatin structure and the transcription activation machinery (45) and induce tumor suppressor gene expression, leading to cancer prevention (46, 47). Finally, the downregulation or inhibition of some growth factors including transforming growth factor-beta (TGF-b) and EGF is also associated with anticarcinogenic activity of genistein (48,49). In insulin-like growth factor-1 (IGF-1)-stimulated PC-3 prostate cancer cells, genistein also inhibited cell growth by suppressing downstream of IGF-1R activation (50). In our previous study, genistein was shown to effectively reverse the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERa and IGF-1 receptor (IGF-1R) signaling pathways upregulated by E2 or BPA (22).

DAIDZEIN The next abundant isoflavone following genistein in soy beans is daidzein, which is 7-hydroxy-3-(4-hydroxyphenyl) chromen-4one. As in the case of genistein, daidzein has been also garnered interest for its antiproliferative and anticancer effects. Previously, daidzein has been shown to be a natural compound capable of inducing tumor cell death in various

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types of cancer such as pancreatic, colon, breast, and ovarian cancers at concentrations over 5 or 10 mM (51–54). Recently, chemopreventive effects of daidzein on prostate cancer have been reported (55–57). Besides, it was investigated that equol, which is converted from daidzein by the intestinal flora (58), also decreased the risk of prostate cancer (59). In general, since equol is known to have a higher affinity to ER than daidzein does, equol producers might be expected to have greater efficacy of daidzein than nonequol producers : people who have plasma equol concentrations of < 40 nmol/L can be classified as nonequol producers; people having concentrations of >83 nmol/L can be defined as equol producers (60). Also, in the productive capacity of equol, Asians are reported to produce significantly higher amount of equol after eating foods containing soy isoflavones than Westerners do (61). In the previous study, equol (5, 10, and 50 mM) and daidzein (0.1, 1, and 5 mM) showed to decrease cell migration and invasion in human prostate cancer DU 145 cells (62). In addition to in vitro cellular models, daidzein exerted its anticancer effects in in vivo animal models. In 7,12-dimethylbenz[a]anthracene administered mice, daidzein represented antihepatic cancer effect by modulating the induction of cytochrome p450 CYP1A1 and CYP1B1 enzymes (63). Also in the previous study, daidzein effectively inhibited the growth of human leukemia HL cells in the subrenal capsules of mice and in diffusion chambers implanted into the peritoneal cavities of mice (64). 9,10-dimethyl-1,2-dibenzanthracene-induced mammary tumors in rats were inhibited by daidzein, and tumor latency was significantly increased in mammary tumor virus-neu mice at concentration ranges of 5250 mg/kg (65, 66). The potential anticancer mechanisms of daidzein can be considered as cell cycle arrest and apoptosis (67). It was shown that daidzein caused cell cycle arrest at G1 and G2/M phases and significantly induced apoptosis by increasing caspase-9 activity and decreasing cyclin D expression (53). Jin et al. (67) revealed that daidzein-induced apoptosis was mediated through the generation of ROS that perturbs mitochondrial function, leading to the increase in mitochondrial permeability, cytochrome C release, and the activation of caspases, which play critical roles in the execution of apoptosis (68). Moreover, daidzein was demonstrated to inhibit ovarian cancer cell growth by inducing apoptosis through caspase-3 activation (53). As a different type of apoptosis, daidzein was found to augment the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptotic death in LNCaP prostate cancer cells (56). In this study, daidzein did not alter the expression of death receptors TRAIL-R1 and TRAIL-R2 but significantly increased TRAIL-induced disruption of mitochondrial membrane potential. Also in prostate cancer, the androgen receptor (AhR) dependent inhibition of CYP1 enzymes, which are involved in carcinogenesis via the activation of procarcinogenic compounds to carcinogenic metabolites, may explain other anticancer mechanisms of daidzein (63, 69). In terms of DNA topoisomerases, daidzein

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was also reported to inhibit the enzyme action, leading to cancer cell death (70). However, in HCT116 human colon carcinoma cells, daidzein did not inhibit Topo II unlike genistein, which induced the decrease in cell proliferation due to its inhibition of this enzyme (37).

RESVERATROL Resveratrol, a trans-3,40 ,5-trihydroxystilbene, is a plantderived polyphenolic stilbene and present in the skin of red grapes, other fruits, peanuts, and dietary supplements (71). Generally, red wine contains resveratrol on the order of 0.1– 14.3 mg/l (72). Resveratrol is categorized as a phytoestrogen due to its capability to compete with natural estrogens for binding to ERa and thus modulating the biological responses exerted by this receptor (73). Although the biological effects of resveratrol remain controversial due to its both estrogenic and antiestrogenic properties depending on cellular environment and the presence of coregulator, broad-spectrum beneficial health effects of resveratrol have been currently emphasized. Especially, resveratrol has obtained much attention due to its potential chemopreventive properties resulting from targeting multiple signaling pathways that promote cancer cell survival and tumor growth (74). Resveratrol can be regarded as an ideal molecule because several reports have shown that it does not damage nonmalignant cells although it may trigger direct cytotoxic effects on cancer cells (75–77). Many studies have demonstrated the antiproliferative and antitumor effects of resveratrol in some human cancers. For instance, resveratrol was found to inhibit the growth of prostate cancer cell lines, LNCaP, DU-145, and PC-3 cells at 2~40 mM (74) and revealed anticancer effect on A549 nonsmall cell lung cancer cells exposed to benzo(a)pyrene at 10 mM (78). In MCF-7 breast cancer cells, resveratrol showed antiproliferative effects by inducing apoptosis through a mitochondria/caspase pathway at concentrations less than 10 mM (79). In addition, resveratrol was found to significantly suppress the BG-1 ovarian cancer cell growth stimulated by E2 or BPA at 50 mM as did genistein in our recent study (80). In addition, resveratrol effectively reversed the BG-1 cell proliferation induced by E2 or BPA via inversely down-regulating the expressions of ERa, IGF-1R, p-IRS-1, p-Akt1/2/3, and cyclin D1 at both transcriptional and translational levels, suggesting that resveratrol is a novel candidate for the prevention of tumor progression caused by BPA via an effective inhibition of the cross-talk of ERa and IGF-1R signaling pathways (81). A previous study reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen (82). In vivo evaluations using animal models also showed that resveratrol effectively inhibited the growth of diverse cancers. Resveratrol inhibited the growth of lung cancer in a dose-dependent manner in nude mice xenografted with A549 cells at the administration levels of 15, 30, and 60 mg/kg (83). In orthotopic PCa xenografts, resveratrol

significantly inhibited tumor growth, progression, local invasion, and spontaneous metastasis of prostate cancer at 50 mg/ kg (84). Resveratrol-bovine serum albumin nanoparticles represented anticancer activity on xenografted nude mice at 50, 100, and 200 mg/kg, which were established by injecting a suspension of the human primary ovarian cancer cells, SKOV3 (85). Underlying mechanisms facilitated by resveratrol have been investigated with its chemopreventive actions. As a potential antioxidant, resveratrol has been shown to exert a strong inhibitory effect on the formation of free radicals and to reduce oxidative stress in PC-3 and DU-145 cells, leading to decrease the growth of prostate cancer (86). Resveratrol-mediated apoptosis is a main mechanism of its chemopreventive action. This type of apoptosis is associated with the activation of p53, a cellular tumor antigen or a tumor suppressor, and the induction of death receptor Fas/CD95/APO-1 in various cancer cells (87). For some cancer cell lines, such as breast cancer MCF-7, adenocarcinomic alveolar basal epithelia A549, and non-small lung cancer H460, resveratrol reduced the viability of these cell lines in a dose- and a time-dependent manner by partially increasing p53 protein level and involving the activation of caspases 9 and 7 and the cleavage of poly (ADP) ribose polymerase (PARP) (88). A significant increase of Fas ligand and Fas-associated protein with death domain by resveratrol was shown to mediate apoptosis and cell death in MCF-7 breast cancer cells (42). Other antitumor mechanisms of resveratrol include modulation of the transcription factor NF-kB (89, 90), inhibition of the cytochrome P450 isoenzyme CYP1A1 (91), alterations in androgenic actions (86, 92), and expression and activity of cyclooxygenase (COX) enzymes (93). Current preclinical and mechanistic data available from

TABLE 1 Chemopreventive mechanisms of genistein, daidzein, and resveratrol Phytoestrogen Genistein

Daidzein

Resveratrol

Mode of action

Ref.

PTK inhibition Topoisomerase inhibition Antioxidant property Epigenome modification Growth factor signaling downregulation Apoptosis CYP1 inhibition Topoisomerase inhibition Antioxidation Apoptosis NF-kB modulation CYP1 inhibition COX modulation

28, 30–31 33–37 28, 38–41 44–47 22, 48–50, 53, 56, 67 63, 69 70 86 42, 87, 88 89, 90 91 93

ANTIPROLIFERATIVE EFFECT OF PHYTOESTROGENS ON CANCERS

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TABLE 2 Chemopreventive effects of genistein, daidzein, and resveratrol in laboratory animals Animal

Dose

Balb/c mouse

Genistein, 100 mg/kg/day

8 wk

Balb/c & C57BL/ 6 mouse

Genistein, 10 mg/kg/day

5 days

Nude mouse

12 wk

SD rat

Soy bean chips,10~20% (wt/wt) in diet Genistein, 25, 250 mg/kg diet

ICR mouse

Daidzein, 5, 25 mg/kg

SD rat

Daidzein, 200 mg/kg in diet

MMTV-neu mouse Daidzein, 250 mg/kg in diet Nude mouse Nude mouse

Nude mouse

Resveratrol, 15, 30, 60 mg/ kg/day Resveratrol, 50 mg/kg/day

Resveratrol, 50, 100, 200 mg/ kg/wk

Exposure time Administration

21 days

4 wk 120 days

34 wk 15 days 8 wk

4 wk

Major outcome

Intraperitoneal injection Inhibition of BPA-induced ovarian cancer growth Intraperitoneal injection Inhibition of mammarycarcinomainduced angiogenesis Feeding Inhibition of lung metastasis of breast cancer Feeding Suppression of DMBAinduced mammary tumor development Oral administration Inhibition of DMBA-induced carcinogenesis Feeding Reduction in DMBA-induced mammary tumor multiplicity Feeding Delay of mammary tumorigenesis Intravenous injection Inhibition of lung cancer growth Intraperitoneal injection Inhibition of prostate tumor growth, progression, and metastasis Intraperitoneal injection Inhibition of ovarian tumor growth

Ref. 22 25

26 27

63 65

66 83 84

85

SD D Sprague-Dawley.

numerous in vitro and in vivo studies can be implied to support anti-cancer effects of resveratrol to apply its potential as an anticancer agent in human populations (71).

CONCLUSION Genistein and daidzein, the 2 predominant isoflavones in soy products, and resveratrol derived from grapes and other vegetables are the most potent phytoestrogens that can be used for chemopreventive purposes against cancers because a great number of evidences have supported their efficacies. In addition to their excellent anticancer activity, low cytotoxicity for normal cells and easy ingestion from diet might spur the development of natural therapeutic agents including phytoestrogens. However, the controversies about their chemopreventive effect have existed due to some negative reasons (52,94). For genistein, it stimulates cancer cell growth at low concentration (10 mM) (95). This fact poses concern that plasma phytoestrogen concentrations of >10 mM cannot be achieved by dietary intake, and thus low phytoestrogen levels in the body may stimulate cancer growth. The

serum levels of >10 mM cannot be attainable even in Asian people who consume a respectable amount of phytoestrogens. In fact, the average value of plasma daidzein and genistein concentration of Japanese women who intake high isoflavone diet including tofu, natto, and miso was merely 72.46 and 206.09 nmol/L (0.07 and 0.2 mM), respectively (96). For resveratrol, it was also known to have poor bioavailability from the measurement of circulating levels in the body (97). In spite of those facts, the epidemiological study definitely shows that the incidence of some cancers is much lower in Asians than Westerners as referred above. Therefore, besides the serum levels of phytoestrogens, other factors such as tissue phytoestrogen concentration, which is currently unknown, and the timing of exposure to phytoestrogenic compounds are needed to be known (95). In addition, because the synergistic effect of mixed intake of phytoestrogens from daily diet strengthens the chemopreventive efficacies (95, 98), the serum concentration of each phytoestrogen may not be an absolute factor for estimating anticancer effects of phytoestrogens in vivo. As reviewed in this article, each phytoestrogen has its own ingenious or common chemopreventive mechanism (Table 1) and actually shows anticarcinogenic effects by inhibiting

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chemically induced tumor development or cancer progression in in vivo animal studies as shown in Table 2. Another remarkable point is that various modes of action of phytoestrogens have been successively found these days. For instance, genistein has been found to induce epigenetic modifications such as DNA methylation and histone acetylation, leading to cancer cell death. The possibility of genistein and daidzein to act as Topo poison was also presented. Along with general mechanisms such as antioxidant property and apoptosis, newly elucidated anticarcinogenic modes of action can raise statue of phytoestrogens as a promising reagent for cancer chemoprevention and/or treatment. Another point of this article is that genistein can be a candidate to negate the tumor progressive risk of BPA, a chemical EDC, by suppressing the crosstalk between ERa and IGF-1R signaling pathways. The removal of the carcinogenic risk of EDCs may be anticipated from a diet of phytoestrogens. Future studies on phytoestrogens may be needed to focus on the estimation for humans and to provide the natural strategies against cancers.

FUNDING This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) of the Republic of Korea (2014R1A1A2055295).

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