Gamma tocotrienol and tocopherol-mediated cells death occurs through the production of 15-HETE in prostate cancer cells.

A106

Dietary vitamin E exists as either tocopherols or tocotrienols. Evidence indicates that vitamin Es other than α-tocopherol, may be potent cancer preventive agents. Growth arrest of the PC-3 prostate cancer cell lines was compared in the presence of dietary α-, γ-, and δ-vitamin E by the MTT assay. Physiological concentrations of γ-tocotrienol were tested for apoptotic potential using fluorescent microscopy. QPCR, Western blot, PPAR γ dominant negative and scintillation proximity assays were used to determine the effects of vitamin E on PPAR γ. The effect of vitamin E on 15-S-HETE was determined using ELISA. Tocotrienols induced more growth arrest than tocopherols. The gamma isoforms demonstrated selectivity for growth inhibition toward the cancer cells versus normal prostate epithelia. In PC-3 cells, cell death occurs with 1 µM at 24 hours and apoptosis occurs with 5 µM at 72 hours. PPAR γ was up regulated by dietary γ-vitamin Es. Dietary γ-vitamin E mediated growth arrest was demonstrated to be PPAR γ-dependent using a PPAR γ dominant negative vector. Neither γ-vitamin Es are direct PPAR γ ligands. Concentrations of 15-S-HETE in PC-3 cells were found to be up regulated by treatment with R-γ tocotrienol. These data support that tocotrienols could be more effective as prostate chemopreventive agents than tocopherols. As the γ-vitamin Es are not direct PPAR γ ligands, and 15-S-HETE is up regulated, our data suggest that R-γ-tocotrienol modulates arachidonic acid metabolism by up regulation of 15-S-HETE which induces the PPAR γ pathway, potentiating apoptosis.