Tocotrienols, unsaturated forms of
vitamin E, inhibit the proliferation of a variety of
cancer cells and suppress angiogenesis. However, the mechanisms underlying those effects on
cancer cell growth remain unclear especially under hypoxic conditions. In this study, we demonstrated that δ-
tocotrienol (δ-T3) could be used as a novel
anticancer agent against human colorectal
adenocarcinoma (DLD-1) cells under both normoxic and hypoxic conditions. δ-T3 inhibited the growth of DLD-1 cells in a dose-dependent fashion by inducing cell cycle arrest and apoptosis. This effect was more potent under hypoxic than normoxic conditions. The anticancer effect of δ-T3 was achieved by its up-regulation of
cyclin-dependent kinase inhibitors (p21 and p27), the activation of
caspases and the suppression of phosphorylation of
protein kinase B (Akt) at Thr(308) and Ser(473). In in vivo studies,
oral administration of rice bran
tocotrienol (RBT3, mainly γ-T3) (10 mg/mouse/day) significantly inhibited
tumor growth in nude mice. In
tumor analyses, RBT3 activated p21, p27,
caspase-3 and
caspase-9 and decreased Akt phosphorylation. Furthermore, immunostaining revealed that RBT3 decreased the number of cells positive for CD31/
platelet endothelial cell adhesion molecule-1 in microvessels in the
tumor. Taken together, these data suggest that
tocotrienols are potent
antitumor agents capable of inducing apoptosis and inhibiting angiogenesis under both hypoxic and normoxic conditions.
Tocotrienols could have significant therapeutic potential in the clinical treatment of
tumors.