**7. Isoflavonoids: new insights regarding cancer chemoprevention**

It is very well known that dietary components are, nowadays, considered important therapeutic agents used to prevent various chronic disorders, especially cancer, cardiovascular pathologies and inflammation processes [99]. For example, according to the statistics, the incidence of pros‐ tate cancer or breast cancer in Asian countries has been lower than in Western countries, mainly because of their high consumption of soy products [100]. Furthermore, the incidence of breast cancer in Asian women who had immigrated to Western countries proved to be similar to that of Western women [101]. In addition, soy isoflavones, with the main representative genistein, proved to be promising phytotherapeutic drugs with chemopreventive effects in chronic disorders caused by exposure to solar UVB radiations, including nonmelanoma skin cancer [102, 103].

The cardiovascular diseases are more frequent in women after menopause, due to the modifications in the production of estrogen [88]. Compounds with estrogenic properties, such as the isofla‐ vones found in soy, were evaluated for their potentially cardioprotective activity [89, 90]. The administration of 80 mg/day isoflavones extracted from soybeans for 12 weeks in patients with primary or recurrent ischemic stroke determined a decrease in high sensitivity, C‐reac‐ tive protein and improved vascular endothelial function [68]. A meta‐analysis evaluating the results of nine trials concluded that isoflavone supplementation improves endothelial func‐ tion in postmenopausal women that presents low flow‐mediated dilatation (FMD) levels, but not in ones with high baseline FMD levels [89]. Nevertheless, the benefits of isoflavones regarding the protective effects in ischemic stroke are questionable. Yu et al. associated the high intake of soy isoflavones (53.6 mg isoflavones/day) with an increase in the risk of ischemic

The protective effect against the inflammatory vascular disease of isoflavones is due to their anti‐inflammatory activity. The inhibition of monocyte adhesion to endothelial cells that involves the activation of PPARγ is related to this effect [66]. The anti‐inflammatory properties are due to inhibition of interleukin‐6 (IL‐6), interleukin‐12 (IL‐12), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α) production, NF‐κB regulation and their antioxidant activity [92]. Pro‐oxidant effects at high doses were also noticed for these compounds. The supple‐ mentation with 640 mg/kg daidzein in pigs revealed antioxidant properties in muscle, but

Administration of soy isoflavones (daidzein, genistein and glycetin) in capsules, 20 mg twice daily in female patients improved irritable bowel disease and association with vitamin D can determine a synergistic effect [94]. The estrogen‐like effects of isoflavones genistein and daidzein seem to be involved in their beneficial effects on sleep status. A high intake of isoflavones was related to an optimal sleep duration and an increased quality of sleep in

Age‐related skin modifications in women emerging with a decline in estrogen production can be reduced by isoflavones. Genistein improves skin appearance and is used to reduce wrinkles and skin dryness in cosmetic preparations. It increases the skin resistance and

Anti‐bacterial effects were also reported for isoflavones. For instance, biochanin A, a methylated isoflavone from red clover, inhibits the growth of *Chlamydia trachomatis* and *Chlamydia pneumoniae* [97]. Isoflavones act as anti‐viral agents against several types of viruses including herpes simplex virus and human immunodeficiency virus (HIV). Genistein, a tyrosine kinase inhibi‐ tor, is one of the compounds most studied for these properties and revealed positive effects in inhibiting HIV‐1 infection, especially when applied in entry and early post‐entry stages [98].

It is very well known that dietary components are, nowadays, considered important therapeutic agents used to prevent various chronic disorders, especially cancer, cardiovascular pathologies

**7. Isoflavonoids: new insights regarding cancer chemoprevention**

were accompanied by pro‐oxidant effects in fat and liver tissues [93].

stroke in women [91].

268 Flavonoids - From Biosynthesis to Human Health

Japanese adults [95].

contributes to skin reparation [96].

Genistein has been extensively studied in different types of cancers cells and cancer animal models [104]. Unfortunately, the low oral bioavailability of genistein [105], due to its high lipophilicity and its extensive metabolism by the phase II enzymes [106], has limited its use in clinical trials [107].

The data regarding the chemopreventive effects of daidzein are limited, more studies being focused on the curative effect of daidzein in cancer and not in its prophylactic properties [108].

Previous *in vitro* evidences have shown that genistein may act not only as an agonist, but also as an antagonist on cancer cells depending on both its concentration and the type of cancer cells on which was tested [109]. In this regard, genistein because of its biphasic effect may be involved not only in preventing, but also in promoting cancer [110].

The *in vitro* chemopreventive effect of genistein might be related to its involvement in epigenetic regulations of gene expression, having a direct effect on histone modifications and DNA methylation [111]. Genistein is also a strong inhibitor of the tyrosine kinase [112] and topoisomerase activities [113]. The *in vitro* apoptotic effect of genistein may be related to the inactivation of NF‐kB and Akt signaling pathways [114], although its specific mechanisms of inducing apoptosis have not being fully understood [115]. According to a previous *in vitro* study on pancreatic cancer cells, genistein suppressed the ovarian cancer cell growth and migration through the inhibition of mRNA [116]. The chemopreventive properties of genistein have also been proved on MCF‐7 breast cancer cells, in which genistein has inhibited the cell proliferation by inactivating the IGF‐1R‐PI3 K/Akt pathway and decreasing the Bcl‐2/ Bax mRNA and protein expressions [115]. Another mechanism responsible for the chemopre‐ ventive effects of genistein might consist in the suppression of the microsomal CYP1a1 gene expression in Hepa‐1c1c7 liver cancer cells [117].

The association between genistein and daidzein has proved antiproliferative effects on human colon adenocarcinoma grade II cell line (HT‐29) [118], the anticancer effect of daidzein being related to copper‐dependent pathway and redox cycle [108].

Among the soy isoflavones, GLY has been the most potent activator of extracellular signal‐ regulated kinase (ERK1/2), exhibiting a significant antiproliferative effect on RWPE‐1 nontu‐ morigenic prostate epithelial cells [119]. Thus, according to another study on the same type of cells, GLY has also shown to decrease the expression of cytokeratin 18 and prostate‐specific antigen (PSA) [120].

Furthermore, *in vivo* data have shown that oral consumption of genistein during the early prepubertal period decreased the susceptibility of developing breast cancer later in life [121]. Genistein, as a phytoestrogen, may interact with the estrogen receptors. In this regard, a previous study on HER2 overexpressing mice has shown that genistein mimicked the estradiol effects, in the presence of estrogen receptor alpha [112], while in postmenopausal women, in the absence of estradiol, genistein directly reduced the anticancer activity of cisplatin, a cytostatic drug commonly used in breast cancer [122]. For instance, according to Tonetti et al. *in vitro* and *in vivo* studies, the concomitant administration of tamoxifen with genistein or daidzein might not be safe because this association has produced bigger size tumors than tamoxifen alone [123].

Soy isoflavones exhibited *in vivo* protective effects against skin chronic disorders including cancer by reducing pro‐inflammatory cytokines and oxidative stress and through activation of NF‐kB [124]. For example, genistein has suppressed UV‐induced skin carcinogenesis in mice through its moderate inhibitory effect on ornithine decarboxylase activity [125]. Moreover, 7,3′,4′‐trihydroxyisoflavone, a major metabolite of daidzein, has reduced UVB‐induced skin cancer in mice through inhibition of cyclooxygenase‐2 (COX‐2) expression by suppress‐ ing NF‐kB transcription activity [103]. In this regard, genistein loaded‐PLA nanocapsules indicated to be a promising formulation with chemopreventive effects against skin cancer in porcine ear skin not only by increasing the penetration of genistein in skin deeper layers, but also by limiting its degradation in time [107].

According to Ghaemi et al. study on human papillomavirus (HPV) associated‐cervical can‐ cer in mice, genistein has also indicated immunomodulatory effects through increment of interferon‐gamma (IFN‐gamma) level, lymphocyte proliferation and lactate dehydrogenase (LDH) release [126].

Consequently, the isoflavones from soy products may be considered promising alternative therapies to prevent various types of cancer, more experimental and clinical studies being necessary for establishing the safe dose that can be used especially in patients susceptible to hormone‐dependent tumors.
