Combination of vitamin E and selenium synergistically inhibits proliferation and induces apoptosis of prostate cancer cells via modulations in Bcl-2 family proteins

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Preclinical, epidemiological, and phase III data from randomized, placebo-controlled clinical trials suggest that both selenium and vitamin E have potential efficacy in Prostate Cancer (PCa) chemoprevention. Based on these studies, the Selenium and Vitamin E Chemoprevention Trial (SELECT) has recently been initiated. It is a randomized, prospective, double-blind study designed to determine whether selenium and vitamin E alone and in combination could reduce the risk of PCa among healthy men. This is an outstanding effort of its kind; however, several investigators are critical about the rationale and two concerns are often raised are: 1) whether researchers are acting too quickly or whether there are sufficient data on these supplements to justify this trial; and 2) whether more biomarkers (which could suggest the possible molecular mechanisms involved) should be included in SELECT trial. In this study, employing in vitro cell culture system, we examined the effect of vitamin E (+α-tocopherol succinate) and selenium (methylselenic acid), alone or in combination, on human PCa cells (LNCaP, DU145 and PC-3) and normal human prostate epithelial cells (PrEC). The cells were treated with vitamin E (1 and 5 μM), selenium (1 and 2 μM) alone or in combination and the effect of treatments were evaluated in these cells. Our data demonstrated a modest decrease in viability, cell growth and colony formation ability of the cancer cell lines at the higher concentrations of vitamin E (5 μM) and selenium (2 μM). However, the combination of these two agents resulted in a dramatic and significant increase in the observed anti-proliferative responses. Interestingly, neither of the two agents nor a combination was found to cause any appreciable effect on the growth of normal PrEC cells. Further, a combination of the two agents also resulted in a significant i) decrease in the proliferating cell nuclear antigen, ii) induction of apoptosis, and iii) increase in Bax/Bcl-2 ratio, in the PCa cells. Because serum PSA is considered to be an important marker for identifying prostate adenocarcinoma, we also determined the effect of vitamin E and selenium (alone or in combination) on PSA levels in androgen-responsive human prostate carcinoma LNCaP cells. Our data demonstrated that a combination of vitamin E and selenium resulted in a better, at-least an additive, PSA-inhibitory response than either of the agents alone. The combination of vitamin E and selenium also resulted in a synergistic inhibition of NF-κB/p65 (in the nucleus) with a concomitant increase of IκB-α (in cytosol) in LNCaP cells. This study suggested that i) a combination of vitamin E and selenium imparts a better anti-proliferative response compared to either of these agents alone, and ii) these effects may be mediated, at least in part, via modulations in Bax/Bcl-2 family of protein and/or NF-κB pathway.