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Nutrition and Disease

Tocotrienol Inhibits Secretion of Angiogenic Factors from Human Colorectal Adenocarcinoma Cells by Suppressing Hypoxia-Inducible Factor-1^1–3,

⁴ Food and Biodynamic Chemistry Laboratory and ⁵ Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan and ⁶ Department of Pharmacology, Institute of Health Biosciences, University of Tokushima, Tokushima 770-8503, Japan

^* To whom correspondence should be addressed. E-mail: nkgw{at}biochem.tohoku.ac.jp.

Tocotrienol (T3), unsaturated vitamin E, has recently gained considerable attention as a potent antiangiogenic agent minimizing tumor growth, the exact intracellular mechanisms of which remain poorly understood. Because hypoxia-inducible factor-1 (HIF-1), its downstream target vascular endothelial growth factor (VEGF), and other angiogenic factors such as interleukin-8 (IL-8) and cyclooxygenase 2 (COX-2) play critical roles in neovascularization, we tested the hypothesis that the inhibitory effect of T3 on tumor angiogenesis is via regulation of these angiogenic factors. We used 2 cancer cell lines, human colorectal adenocarcinoma cells (DLD-1) and human hepatoma cells (HepG2). T3 isomers (2 µmol/L) inhibited hypoxia-induced VEGF secretion from DLD-1, with -T3 showing potent inhibition. -T3 suppressed hypoxia-induced VEGF and IL-8 expression in DLD-1 at both mRNA and protein levels, and we found the inhibitory mechanism of -T3 by reducing HIF-1 protein expression or increasing HIF-1 degradation. Also, -T3 (2 µmol/L) did not affect hypoxia-induced COX-2 mRNA expression; however, -T3 tended to suppress (P = 0.044) hypoxia-induced COX-2 protein expression, implying a possible post-transcriptional mechanism by -T3. Overall, our results confirmed that T3 has an inhibitory effect on angiogenic factor secretion from cancer cells and revealed the possible mechanisms, providing new information about the antiangiogenic effects of T3.