Equol and genistein enhance the apoptotic effects of γ- and δ-tocotrienols in androgen receptor-positive prostate cancer cells

Prostate cancer is one of the most common male cancers in Western countries, yet the incidence of this fatal disease remains low in Asian populations. Environmental factors such as diet play an important role in cancer etiology, and a high phytoestrogen intake may be one factor contributing to the low prostate cancer mortality in men of Asian origin. In this study, we investigated the effects of each of the two vitamin E isoprenoids γ-, or δ-tocotrienol, (commonly found in rice) combined with each of the phytoestrogens genistein or daidzein (found in soybeans) or the daidzein metabolite equol, on cell growth and apoptosis of five human prostate tumor cell lines. The cell lines included in this study are the androgen receptor-positive (AR+) LNCaP, VCaP and PC3-AR and the androgen receptor-negative (AR-) PC3 and DU-145. We found that γ-tocotrienol inhibited the growth of all five-cell lines in a dose-dependent manner. However, morphologic features of apoptosis and caspase-3 activation were limited to the AR+ cells. δ-tocotrienol, similarly to γ-tocotrienol, induced apoptosis selectively in the AR+ cells. Both γ- and δ-tocotrienol increased caspase-3 activity in a dose-dependent manner in AR+ but not in AR- cells. Genistein and equol enhanced the effects of γ- or δ-tocotrienol on caspase-3 activation whereas daidzein had no effect. These results show clearly that the antiproliferative and apoptotic effects of tocotrienols are augmented by genistein or equol. However, these effects are limited to AR+ cells, suggesting a requirement of the AR receptor for the induction of the apoptotic process. Interestingly, the combinations of genistein and equol with γ- or δ-tocotrienol had no effect on normal prostate cells (RWPE-1). This is the first report, to our knowledge, demonstrating that components of soy enhance the anticancer effects of γ- and δ-tocotrienols.

Acknowledgements: This research was funded by the Cyprus Research Promotion Foundation (grant number 0505/20).