Gamma-tocotrienol induces apoptosis and necrosis in human prostate cancer cell lines

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We have previously shown that gamma-tocopherol, the major form of vitamin E in US diets, but not alpha-tocopherol, the major vitamin E form in tissues and supplements, induced cell death in androgen-sensitive prostate cancer (LNCaP) cells, but not androgen non-responsive PC-3 cells, by interrupting sphingolipid biosynthesis [Jiang et al (2004) PNAS, 101, 17825-30]. We currently showed that gamma-tocotrienol, another form of vitamin E that is mainly found in palm oil, induced cell death in both LNCaP and PC-3 cells. Gamma-tocotrienol appeared to induce apoptosis and necrosis in LNCaP and PC-3 cells, as indicated by annexin V and propidium iodide staining using flow cytometry. Gamma-tocotrienol treatment led to cytochrom C release and PARP cleavage in both PC-3 and LNCaP cells. Although gamma-tocotrienol induced activation of caspase-9 and caspase-7 in LNCaP cells, there was no apparent caspase activation in PC-3 cells. Interestingly, although PC-3 was more resistant than LNCaP to many apoptosis-inducing agents including staurosporine, PC-3 appears to be more sensitive than LNCaP to tocotrienol-induced death. Consistently, more gamma-tocotrienol was found in PC-3 than in LNCaP. Our preliminary data also showed that similar to gamma-tocopherol, gamma-tocotrienol caused accumulation of dihydrosphingosine and dihydroceramide in LNCaP cells, suggesting an interruption of sphingolipid de novo synthesis. However, unlike gamma-tocopherol, myriosin, an inhibitor of de novo synthesis of sphingolipids, did not significantly reverse cell death caused by tocotrienol. Studies are undertaken to further characterize the mechanisms of tocotrienol-induced cell death in both cell lines, and to test in vivo anti-cancer effect in nude mice implanted with prostate cancer cells. (Supported by NIH 7 R01AT001821)