Anti-angiogenic function of tocotrienol.
Angiogenesis means the formation of new blood vessels from preexisting vascular, is of fundamental importance in several pathological states such as tumor growth, rheumatoid arthritis, and diabetic retinopathy. Angiogenesis involves a set of steps, including activation and movement of endothelial cells and tube formation. Control of these steps by drugs or dietary food components is a hopeful approach for the prevention of angiogenic disorders. Based on these backgrounds, we searched the anti-angiogenic food components. As a result, we found that tocotrienol (T3), especially delta, beta, and gamma-T3 has the potent anti-angiogenic activity in vitro and in vivo experiments. T3, which is rich in rice bran and palm oil, inhibited growth factor-induced proliferation, migration and tube formation in human umbilical vein endothelial cells. T3 showed inhibition of tumor cell-induced angiogenesis in mouse dorsal air sac (DOS) assay. These results indicated that T3 is a potent anti-angiogenesis compound. Tocopherol (Toc) did not inhibit angiogenesis. The anti-angiogenic mechanism of T3 and Toc was evaluated by western blotting. T3 inhibited activation of growth factor-induced extracellular signal-regulated kinase, Akt (protein kinase B), and endothelial nitric oxide synthase (eNOS), which are located downstream of the various growth factor receptors. T3 suppressed phosphorylation of vascular endothelial growth factor (VEGF) receptor 2. These effects were dose-dependent manner. Anti-angiogenic mechanism of T3 mediates inhibition of growth factor induced survival, migration and angiogenesis signals. These findings suggested that T3 may have potential for preventing angiogenic disorders in humans.
Miyazawa
Teruo
T
Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan. miyazawa@biochem.tohoku.ac.jp
Shibata
Akira
A
Nakagawa
Kiyotaka
K
Tsuzuki
Tsuyoshi
T
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005346:Fibroblast Growth Factors; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D024508:Tocotrienols / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D024508:Tocotrienols; D005346:Fibroblast Growth Factors