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: Although cell-based studies have shown that [gamma]-tocotrienol ([gamma]TE) exhibits stronger anticancer activities than other forms of vitamin E including [gamma]-tocopherol ([gamma]T), the molecular bases underlying [gamma]TE-exerted effects remains to be elucidated. Here we showed that [gamma]TE treatment promoted apoptosis, necrosis and autophagy in human prostate PC-3 and LNCaP cancer cells. In search of potential mechanisms of [gamma]TE-provoked effects, we found that [gamma]TE treatment led to marked increase of intracellular dihydroceramide and dihydrosphingosine, the sphingolipid intermediates in de novo sphingolipid synthesis pathway but had no effects on ceramide or sphingosine. The elevation of these sphingolipids by [gamma]TE preceded or coincided with biochemical and morphological signs of cell death and was much more pronounced than that induced by [gamma]T, which accompanied with much higher cellular uptake of [gamma]TE than [gamma]T. The importance of sphingolipid accumulation in [gamma]TE-caused fatality was underscored by the observation that dihydrosphingosine and dihydroceramide potently reduced the viability of both prostate cell lines and LNCaP cells, respectively. In addition, myriosin, a specific inhibitor of de novo sphingolipid synthesis, counteracted [gamma]TE-induced cell death. In agreement with these cell-based studies, [gamma]TE inhibited LNCaP xenograft growth by 53% (p < 0.05), compared to 33% (p = 0.07) by [gamma]T, in nude mice. These findings provide a molecular basis of [gamma]TE-stimulated cancer cell death and support the notion that elevation of intracellular dihydroceramide and dihydrosphingosine is likely a novel anticancer mechanism.

Copyright (C) 2012 John Wiley & Sons, Inc.