Induction of Caspase-Independent Programmed Cell Death by Vitamin E Natural Homologs and Synthetic Derivatives

Current observations in the literature suggest that vitamin E may be a suitable candidate for cancer chemotherapy. To investigate this further, we examined the ability of the vitamin E natural homologs [alpha-, beta-, gamma-, delta-tocopherols (alpha-TOC, beta-TOC, gamma-TOC, delta-TOC) and alpha-, beta-, gamma-, delta-tocotrienols (alpha-TT, beta-TT, gamma-TT, delta-TT)] and their corresponding succinate synthetic derivatives [alpha-, beta-, gamma-, delta-tocopheryl succinates and alpha-, beta-, gamma-, delta-tocotrienyl succinates (alpha-TS, beta-TS, gamma-TS, delta-TS)] to induce cell death in AR- (DU145 and PC3) and AR+ (LNCaP) prostate cancer cell lines. The most effective of all the natural homologs of vitamin E was determined to be delta-TT, whereas delta-TS was the most potent of all the natural and synthetic compounds of vitamin E examined. Both gamma-TT and delta-TT induced caspase activity selectively in AR+ LNCaP cells, suggesting a possible role for AR for the activation of caspase-dependent programmed cell death (CD-PCD). More important, however, gamma-TT, delta-TT, gamma-TS, and delta-TS activated dominant caspase-independent programmed cell death (CI-PCD) in all prostate cancer cell lines examined. Thus, vitamin E homologs and synthetic derivatives may find applications in the treatment of prostate tumors that are resistant to caspase-activating therapeutic agents.