Combination of Vitamin E and Selenium Causes an Induction of Apoptosis of Human Prostate Cancer Cells by Enhancing Bax/Bcl-2 Ratio

BACKGROUND. The Selenium and Vitamin E Chemoprevention Trial (SELECT) is aimed at determining the usefulness of a combination of vitamin E and selenium for Prostate cancer (PCa) prevention in humans. The aim of this study is to evaluate the efficacy and mechanistic basis of this combination. METHODS. We determined the effect of vitamin E (+-alpha-tocopheryl succinate, VES) and selenium (methylselenic acid, MSA), alone and in combination, on the proliferation of LNCaP, DU145, and PC-3 cells as well as normal prostate PrEC cells. We also determined the involvement of Bcl-2 family proteins as a mechanism of the biological effects of vitamin E and selenium combination. RESULTS. VES or MSA alone led to a modest inhibition in the viability and growth of PCa cells. However, a combination of these two agents resulted in a dramatic increase in growth inhibition of PCa cells. Interestingly, VES and/or MSA were not found to have any effect on the growth or viability of normal PrEC cells. VES and MSA treatment to human PCa cells resulted in (i) induction of apoptosis, (ii) increase in Bax, Bak, and Bid proteins, and (iii) decrease in Bcl-2 protein. Furthermore, Bax knockdown via shRNA and Bcl-2 overexpression via Bcl-2 plasmid resulted in a rescue of PCa cells from apoptosis. CONCLUSIONS. Our study suggested that vitamin E and selenium combination maybe more effective than either of these agents alone. Further, our data demonstrated a causal connection between Bax and Bcl-2 modulation and induction of apoptosis by VES and MSA combination. Prostate 68: 1624-1634,2008. (C) 2008 Wiley-Liss. Inc.