Abstract
BackgroundSoy phytoestrogens, such as daidzein and its metabolite equol, have been proposed to be responsible for the low breast cancer rate in Asian women. Since the majority of estrogen receptor positive breast cancer patients are treated with tamoxifen, the basic objective of this study is to determine whether equol enhances tamoxifen’s anti-tumor effect, and to identify the molecular mechanisms involved.MethodsFor this purpose, we examined the individual and combined effects of equol and tamoxifen on the estrogen-dependent MCF-7 breast cancer cells using viability assays, annexin-V/PI staining, cell cycle and western blot analysis.ResultsWe found that equol (>50 μM) and 4-hydroxy-tamoxifen (4-OHT; >100 nM) significantly reduced the 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. These compounds also induced a marked reduction in the bcl-2:bax ratio, which was accompanied by caspase-9 and caspase-7 activation and cytochrome-c release to the cytosol. Taken together, these data support the notion that the combination of equol and tamoxifen activates the intrinsic apoptotic pathway more efficiently than each compound alone.ConclusionsConsequently, 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.
Highlights
Soy phytoestrogens, such as daidzein and its metabolite equol, have been proposed to be responsible for the low breast cancer rate in Asian women
Equol and 4-OHT induce MCF-7 cell death via apoptosis We began evaluating the mechanism implicated in the reduction of MCF-7 cell viability by determining cell death following treatment with equol and 4-OHT
We found that equol and 4-OHT induced a time-dependent reduction in the total levels of bcl-2 in MCF-7 cells, whereas they did not affect bax expression (Figure 6)
Summary
Soy phytoestrogens, such as daidzein and its metabolite equol, have been proposed to be responsible for the low breast cancer rate in Asian women. Equol (7-hydroxy3-(4′-hydroxyphenyl)-chroman) is the bioactive metabolite of daidzein, a major phytoestrogen found in soy an inhibitory effect at high concentrations (50–100 μΜ) [14]. As the role of equol in relation to breast cancer remains unclear, this study was designed to delineate the effect of equol on estrogen-dependent breast cancer cells using MCF-7 cells as a model system. This is important as the controversy of results obtained in the soy isoflavone human intervention studies and the inability to establish the beneficial effects of soy isoflavones could be attributed to the failure to distinguish between “equol producers” and “non-equol producers” [10,19]. The significance of evaluating the therapeutic potential of equol becomes more evident and may facilitate the design and implementation of future equol intervention studies for cancer
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