Cancer: Breast, prostate
Action: Enhances tamoxifen, radio-sensitizer
Daidzein & Genistein Concentrations; Breast Cancer
A systematic search by Mário L de Lemos (2001) through primary English-language literature on MEDLINE (1966–January 2001), EMBASE (1982–January 2001) and Current Contents (1998–January 2001) found that genistein and daidzein at low concentrations were found to stimulate breast tumor growth in in vitro and in vivo animal studies, and antagonize the anti-tumor effect of tamoxifen in vitro. However, at high concentrations, genistein inhibited tumor growth and enhanced the effect of tamoxifen in vitro.
At concentrations below 10 µmol/L, phytoestrogens can stimulate breast tumor growth and antagonize the anti-tumor effects of tamoxifen, particularly in an environment of low endogenous estrogen. In contrast, phytoestrogens inhibit breast tumor growth and enhance the anti-tumor effects of tamoxifen at concentrations above 10 µmol/L (de Lemos, 2002; Akaza et al., 2004).
Breast cancer
Daidzein or its major metabolite equol at a dose molar equivalent to tamoxifen [1.0 mg(2.7 µmol)/kg or 10 mg (27 µmol)/kg/day] was treated orally to rats bearing 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors or ovariectomized athymic nude mice implanted with human MCF-7 breast cancer xenograft and an estrogen pellet. The growth of tumors was monitored for several weeks after the treatment. The cell-cycle and apoptotic stages in mammary tumors collected from rats were analyzed by flow cytometry. Immunohistochemistry analysis was also used to determine the expression of caspase-3.
Oral treatment with daidzein or equol at a human equivalent dose suppressed the growth of both DMBA-induced mammary tumors and human MCF-7 breast cancer xenografts in rodents, the inhibitory activity being superior to that of genistein or tamoxifen. Strong apoptosis induced by daidzein or equol contributes to the anti-tumor potential.
Daidzein and its metabolite equol showed the potential of inhibiting the growth of mammary tumors in rodents. Daidzein or equol could be used as a core structure to design new drugs for breast cancer therapy. Our results indicate that consumption of daidzein may protect against breast cancer (Liu et al., 2012).
Equol Production
S-(-)-equol is a metabolite of the soy isoflavone daidzein and is produced by intestinal bacteria in some, but not in all, humans after soy consumption (Setchell & Clerici, 2010). The ability of S-equol to play a role in the treatment of estrogen or androgen-mediated diseases or disorders was first proposed in 1984 (Setchell et al., 1984). The ability to do so depends on two things: soy and bacteria. First, the soy must contain the soy isoflavone daidzein and the amount may influence equol production. Second, the human must have certain strains of bacteria living within the intestine. Twenty-one different strains of intestinal bacteria cultured from humans have the ability to transform daidzein into S-equol or a related intermediate compound (Setchell & Clerici, 2010).
Several studies indicate that only 25 to 30 percent of the adult population of Western countries produces S-equol after eating soy foods containing isoflavones, (Rowland et al., 2000; Atkinson et al., 2005) significantly lower than the reported 50–60% frequency of equol-producers in adults from Japan, Korea, or China (Song et al., 2006).
Equol Production; Prostate Cancer
Akaza et al. (2004) recently conducted a case-controlled study on those who are able to degrade daidzein, a soybean isoflavone, to equol and those without this ability. The incidence of prostate cancer is known to be lower in residents in Japan. On the other hand, American residents in the United States have a markedly higher incidence of prostate cancer.
The number of subjects was 295 in Japan (133 patients and 162 controls), 122 in Korea (61 patients and 61 controls) and 45 in the United States (24 patients and 21 controls). The percentage of equol producers among patients and controls was 29% and 46% in Japan (P = 0.004) and 30% and 59% in Korea (P = 0.001), respectively. The active isoflavone level was markedly lower and the percentage of equol producers was also lower (17% for patients and 14% for controls) for Americans as compared to the Japanese and Koreans.
These results suggest that the ability to produce equol, or equol itself, is closely related to the lower incidence of prostate cancer. The results also suggest that a diet based on soybean isoflavones will be useful in preventing prostate cancer.
Prostate cancer
The age-adjusted incidence rate of prostate cancer (PCa) has been reported to be lower among Asians than Western populations. A traditional Japanese meal., high in soybean products or isoflavones, may be associated with a decreased risk of PCa. Equol, which is converted from daidzein by human intestinal flora, is biologically more active than any other isoflavone aglycone.
Five out of 6 articles showed significant association of isoflavones with a decreased risk of PCa, and two of them consistently showed that equol-producers carry a significantly reduced risk of PCa. Furthermore, 5 human intestinal bacteria that can convert daidzein into equol were identified in the last 5 years. If equol can reduce risk of PCa, a possible strategy for reducing the risk of PCa may be to increase the proportion of equol-producers by changing the intestinal flora to carry an equol-producing bacterium, with dietary alteration or probiotic technology (Sugiyama et al., 2013).
Equol Enhances Tamoxifen
Charalambous, Pitta, & Constantinou (2013) found that equol (>50 µM) and 4-hydroxy-tamoxifen (4-OHT; >100 nM) significantly reduced the breast cancer MCF-7 cell viability. Furthermore, the combination of equol (100 µM) and 4-OHT (10 µM) induced apoptosis more effectively than each compound alone. Subsequent treatment of MCF-7 cells with the pan-caspase inhibitor Z-VAD-FMK inhibited equol- and 4-OHT-mediated apoptosis, which was accompanied by PARP and α-fodrin cleavage, indicating that apoptosis is mainly caspase-mediated.
Equol may be used therapeutically in combination treatments and clinical studies to enhance tamoxifen's effect by providing additional protection against estrogen-responsive breast cancers.
Radio-sensitizer
Sensitivity of cells to equol, radiation and a combination of both was determined by colonogenic assays. Induction of apoptosis by equol, radiation and the combination of both was also determined by acridine orange/ethidium bromide double staining fluorescence microscopy. DNA strand breaks were assessed by Comet assay.
MTT assay showed that equol (0.1-350 µM) inhibited MDA-MB-231 and T47D cell growth in a time- and dose-dependent manner. Treatment of cells with equol for 72 hours (MDA-MB-231) and 24 hours (T47D) was found to inhibit cell growth with IC50 values of 252 µM and 228 µM, respectively. Furthermore, pre-treatment of cells with 50 µM equol for 72 hours (MDA-MB-231) and 24 hours (T47D) sensitized the cells to irradiation. Equol was also found to enhance radiation-induced apoptosis. Comet assay results showed that the radio-sensitizing effect of equol was accompanied by increased radiation-induced DNA damage.
These results suggest for the first time that equol can be considered as a radio-sensitizing agent and its effects may be due to increasing cell death following irradiation, increasing the remaining radiation-induced DNA damage and thus reducing the surviving fraction of irradiated cells (Taghizadeh et al., 2013).
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