title: α-Tocopherol suppresses antiangiogenic effect of δ-tocotrienol in human umbilical vein endothelial cells.
abstract: Recently, tocotrienol (T3), a less well-known form of vitamin E, has gained attention as a potent hypocholesterolemic, anticancer and antiangiogenic agent. However, tocopherol (Toc), a commonly consumed form of vitamin E, has been reported to inhibit T3's effects (hypocholesterolemic and anticancer activity). There has been no report on Toc's effect on the antiangiogenic action of T3 during cotreatment. The aim of this study is to determine if and to what extent Toc affects the antiangiogenic effects of δ-T3 (the most potent isomer). This was achieved through cotreatment of human umbilical vein endothelial cells (HUVECs) with δ-T3 and Toc (α-, β-, γ- and δ-isomers). Toc, especially α-Toc, attenuated δ-T3-induced cytotoxicity and tube degradation in cotreated HUVECs, while α-Toc treatments did not exhibit any effects. A rat aortic ring assay also showed inhibition of δ-T3's antiangiogenic effects by α-Toc. Further, in HUVEC study, cell cycle arrest and proapoptotic gene expression (p21, p27, caspase-3 and caspase-9) which were induced by δ-T3 were decreased by α-Toc treatment. α-Toc also suppressed δ-T3-induced dephosphorylation of vascular endothelial growth factor receptor 2 and Akt pathway proteins. Additionally, uptake of δ-T3 into HUVECs was decreased by α-Toc. Here we demonstrate that α-Toc not only has little antiangiogenic effect on endothelial cells but also reduces the antiangiogenic effects of δ-T3 through modulation of its cellular uptake and of relevant signal transduction pathways. Understanding T3's antiangiogenic effects and interaction with Toc is important for developing medical applications.
authors: Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
authors: Akira
authors: A
authors: Shibata
authors: Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan. Electronic address: nkgw@m.tohoku.ac.jp.
authors: Kiyotaka
authors: K
authors: Nakagawa
authors: Laboratory of Food and Biomolecular Science, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
authors: Tsuyoshi
authors: T
authors: Tsuduki
authors: Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
authors: Teruo
authors: T
authors: Miyazawa
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D024505:Tocopherols / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014810:Vitamin E / Q000009:adverse effects / Q000031:analogs & derivatives*; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D014810:Vitamin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; C082097:tocotrienol, delta; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D024502:alpha-Tocopherol; D024505:Tocopherols
keywords: Angiogenesis; HUVEC; Tocopherol; Tocotrienol; VEGF