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Wenner et al. J Cancer Metastasis Treat 2020;6:33  I  http://dx.doi.org/10.20517/2394-4722.2020.73                      Page 9 of 17

               GENISTEIN
               Genistein is a polyphenolic isoflavone compound derived from soy-based foods. The chemical structure
               of genistein is similar to that of estradiol, indicating its ability to bind to estrogen receptors. Genistein is
               soluble in polar organic solvents and has a lower solubility in water. Epidemiological studies have shown
               an inverse relation of soy-food intake and cancer development, especially in Asian countries where the
               consumption of soy-based foods is high compared to Western countries. Several meta-analyses have found
               that intake of soy foods and soy-based isoflavones is associated with prostate cancer reduction in men
               and breast cancer reduction in both pre- and postmenopausal women. Epidemiological evidence-guided
               research studies aimed at determining the molecular circuitry altered by genistein in cancer prevention
               by employing relevant cellular and animal models. Genistein is typically present in its glycosylated form
               during its biosynthesis in soybeans. After ingestion, deglycosylation occurs i n the small intestine, and the
                                                                                             [58]
               free form of genistein is absorbed in the body resulting in its various pharmacological effects .
               Genistein’s antitumor effects have been extensively investigated in various cancer models including,
               ovarian, breast, prostate, and lung cancers and leukemia and melanoma [10,59] . One of the earlier studies
               that investigated the antitumor properties of genistein in ovarian cancer cells reported the induction of
                                                                             [60]
               apoptosis and autophagocytosis as potential mechanisms of cell death . In that study, A2780 ovarian
               cancer cells were transfected with a GFP-LC3 plasmid and subjected to glucose deprivation or different
               concentrations of genistein. Analysis of cells using fluorescence microscopy revealed recruitment and
               localization of LC3-II to autophagosomes, indicative of an autophagic response. Further experiments in
               the same study demonstrated that nutrient deprivation was an important part of autophagic cell death
                                                       [60]
               induced by genistein in ovarian cancer cells . A study focusing on elucidating the antitumor effects
               of genistein employing A549 lung adenocarcinoma cells concluded that genistein, by inhibition of
               autophagic flux, enhanced tumor necrosis factor-related apoptosis, inducing ligand (TRAIL)-induced cell
                                                                 [61]
               death compared to genistein or TRAIL alone treated cells . Another study usingpancreatic cancer cells
               showed that genistein potentiated the antitumor effect of 5-FU by inducing apoptotic and autophagic cell
               death . That study used both cell culture and pancreatic tumor xenograft models and demonstrated that
                    [62]
               the combination of 5-FU and genistein had superior antitumor effects against the growth of pancreatic
               cancer cells when compared to the groups treated with 5-FU and genistein alone. Analysis of molecular
               mechanisms revealed increased expression of LC3-II, Beclin 1 and decreased levels of Bcl2, a key negative
               regulator of autophagy, which binds to Beclin1 . In addition, the study also confirmed the induction of
                                                        [61]
               autophagic cell death in the group treated with both genistein and 5-FU by using chloroquine, a known
                                  [62]
                                                 [63]
               inhibitor of autophagy . Prietsch et al.  investigated the antiproliferative effects of genistein usingMCF-7
               human breast cancer cells. The study demonstrated that the antitumor effect of genistein involved the
               generation of free radicals, increase in BAX/Bcl-2 ratio, and downregulation of survivin, which ultimately
               resulted in induction of apoptosis and autophagy. Even though the study did not demonstrate the exact
               role of autophagy, LC3-II immunostaining of the cells treated with genistein clearly revealed the induction
                                            [63]
               of autophagy in breast cancer cells . Consumption of genistein (soy products or dietary supplements) was
               shown to have a differential effect in breast cancer cells with a varied ERα/ERβ ratio . Cells with a low
                                                                                         [64]
               ratio were shown to be more susceptible to genistein and increased effectiveness was seen in combination
                                                                      [64]
               with tamoxifen-treated cells by increasing autophagic cell death . In contrast, a high ratio was shown to
               have counterproductive effect in anticancer treatment due to a decrease in ROS production, one of the
               main mechanisms of action of cisplatin (apoptosis) and tamoxifen-treated cells (autophagic cell death) .
                                                                                                       [64]
               A study employing a preclinical model for estrogen receptor positive (ER+) breast cancer showed that
               lifelong genistein intake reduces the risk of de novo and acquired tamoxifen resistance and recurrence of
               tumors. The findings from the study also showed that prepubertal and lifetime genistein consumption
               improved responsiveness to tamoxifen . The antitumor benefits associated with genistein intake was linked
                                               [65]
               to its potential in boosting immunity against tumors, reducing unfolded protein response and pro-survival
                                [65]
               effects of autophagy . Phytochemicals’ ability to work synergistically and/or additively in the presence of
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