delta-Tocotrienol treatment is more effective against hypoxic tumor cells than normoxic cells: potential implications for cancer therapy

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 delta-tocotrienol (delta-T3) could be used as a novel anticancer agent against human colorectal adenocarcinoma (DLD-1) cells under both normoxic and hypoxic conditions. delta-T3 inhibited the growth of DID-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 delta-T3 was achieved by its upregulation of cyclin-dependent kinase inhibitors (p21 and p27), the activation of caspases and the suppression of phospholylation of protein kinase B (Akt) at Thr(308) and Ser(473). In in vivo studies, oral administration of rice bran tocotrienol (RBT3, mainly gamma-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. (C) 2015 Elsevier Inc. All rights reserved.