tocotrienol--delta and Colorectal-Neoplasms

Rice bran is a rich source of functional compounds, including tocotrienol (T3) and ferulic acid (FA). We previously investigated the anti-cancer properties of T3, and reported on the potent inhibitory effects of δ-T3 on angiogenesis and telomerase activity. In this study, we examined the synergistic suppressive effects of the combination of δ-T3 and FA on telomerase activity in DLD-1 human colorectal adenocarcinoma cells. Co-treatment with δ-T3 and FA significantly decreased cellular telomerase activity compared to treatment with δ-T3 alone, whereas FA alone had no inhibitory effect. Co-treatment with δ-T3 and FA also synergistically down-regulated the expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, indicating that the enzymatic activity of telomerase is controlled at the transcriptional level. FA significantly increased the intracellular concentration of δ-T3, suggesting that FA improved the bioavailability of δ-T3, thereby increasing the inhibitory potency of δ-T3 on telomerase. FA may be a promising candidate for augmenting the anti-cancer activity of δ-T3.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Coumaric Acids; Down-Regulation; Drug Synergism; Humans; Telomerase; Vitamin E

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.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 9; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Up-Regulation; Vitamin E

Rice bran chemical profiles differ across rice varieties and have not yet been analysed for differential chemopreventive bioactivity. A diverse panel of seven rice bran varieties was analysed for growth inhibition of human colorectal cancer (CRC) cells. Inhibition varied from 0% to 99%, depending on the variety of bran used. Across varieties, total lipid content ranged 5-16%, individual fatty acids had 1.4- to 1.9-fold differences, vitamin E isoforms (α-, γ-, δ-tocotrienols, and tocopherols) showed 1.3- to 15.2-fold differences, and differences in γ-oryzanol and total phenolics ranged between 100-275ng/mg and 57-146ngGAE/mg, respectively. Spearman correlation analysis was used to identify bioactive compounds implicated in CRC cell growth inhibitory activity. Total phenolics and γ-tocotrienol were positively correlated with reduced CRC cell growth (p<0.05). Stoichiometric variation in rice bran components and differential effects on CRC viability merit further evaluation elucidate their role in dietary CRC chemoprevention.

Topics: Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dietary Fiber; Growth Inhibitors; Humans; Oryza; Phenols; Plant Extracts; Vitamin E

Recent studies have demonstrated that tocotrienol (T3) is superior to tocopherol (Toc) for cancer chemoprevention. However, there is little information on whether Toc influences the anticancer property of T3. In this study, we investigated the influence of Toc on the cytotoxic effects of delta-T3 in DLD-1 human colorectal adenocarcinoma cells. Toc, especially alpha-Toc, attenuated delta-T3-induced cytotoxicity and apoptosis in DLD-1 cells, whereas Toc alone did not exhibit any cytotoxic effect. delta-T3-induced cell cycle arrest and proapoptotic gene/protein expression (e.g., p21, p27, and caspases) were abrogated by alpha-Toc. Furthermore, coadministration of alpha-Toc decreased delta-T3 uptake into DLD-1 cells in a dose-dependent manner. These results indicate that alpha-Toc is not only less cytotoxic to cancer cells, but it also reduces the cytotoxicity of delta-T3 by inhibiting its cellular uptake.

Topics: Adenocarcinoma; alpha-Tocopherol; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Humans; Vitamin E

Recently, tocotrienol (T3), a less well-known form of vitamin E, has gained considerable attention as a potent antiangiogenic agent. However, the majority of vitamin E research has focused on tocopherol (Toc), with some studies indicating alpha-Toc may prevent tumor angiogenesis. In this study, we aimed to clarify the differences in antiangiogenic potential between delta-T3 and alpha-Toc. We showed delta-T3 (2.5-5 microM) completely abolished proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), whereas a similar dose of alpha-Toc had no such effects. delta-T3 suppressed VEGF receptor 2 (VEGFR-2) signaling, and activated caspases in HUVECs. In addition, via an in vivo mouse Matrigel plug angiogenesis assay, we found that delta-T3 (30 microg), but not alpha-Toc, inhibited tumor cell-induced vessel formation. In summary, our results demonstrate delta-T3 has superior antiangiogenic activities to alpha-Toc, and provide insights into the different mechanisms responsible for this effect of T3 and Toc.

Topics: alpha-Tocopherol; Animals; Apoptosis; Caspases; Cell Line, Tumor; Colorectal Neoplasms; Endothelial Cells; Enzyme Activation; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Umbilical Veins; Vascular Endothelial Growth Factor A; Vitamin E