gamma-Tocopherol (gammaT), the predominant form of
vitamin E in diets, but not
alpha-tocopherol, the major
vitamin E form in tissues and supplements, inhibits proliferation of
prostate cancer cells (LNCaP and PC-3) and
lung cancer cells (A549). In contrast, at similar concentrations, gammaT has no effect on normal prostate epithelial cells. Combinations of some
vitamin E forms, such as gammaT and
delta-tocopherol, exhibit additive or synergistic inhibitory effects. In this study, gammaT or its combination with
delta-tocopherol induced apoptosis in
androgen-sensitive prostate LNCaP, but not in
androgen-resistant PC-3 cells, by the induction of
cytochrome c release, activation of
caspase 9 and
caspase 3, cleavage of
poly-ADP-ribose polymerase (PARP), and involvement of
caspase-independent pathways.
Myriocin and
fumonisin B1, specific inhibitors of key
enzymes (
serine palmitoyltransferase and
dihydroceramide synthase, respectively) in de novo synthesis of
sphingolipids, significantly protected cells from gammaT-induced DNA fragmentation,
cytochrome c release, PARP cleavage, and the formation of active
caspase 3. Compared with vehicle-treated controls, gammaT treatment led to pronounced
dihydroceramide and
dihydrosphingosine accumulation, which preceded morphological and biochemical manifestations of apoptosis. In contrast,
ceramide and shpingosine levels did not increase until day 3, when substantial cell death took place. Our study demonstrates that gammaT and mixed
vitamin E forms induce cell death by interrupting the de novo
sphingolipid pathway in a
prostate cancer cell line. Thus, certain
vitamin E forms may be valuable as
anticancer agents.