Tumor anti-angiogenic effect and mechanism of action of delta-tocotrienol.
Anti-angiogenic therapy mediated by drugs and food components is an established strategy for cancer prevention. Our previous cell-culture studies identified a food-derived anti-angiogenic compound, tocotrienol (T3, an unsaturated vitamin E), as a potential angiogenic inhibitor. Among T3 isomers, delta-T3 is considered as the most potent compound. The purpose of this study was therefore to evaluate the inhibitory effect of delta-T3 on tumor angiogenesis. As growth factors (e.g., vascular endothelial growth factor and fibroblast growth factor) play critical roles in tumor angiogenesis, a conditioned medium rich in these growth factors from human colorectal adenocarcinoma cells (DLD-1-CM) was used as an angiogenic stimulus. Delta-T3 (2.5-5 microM) significantly suppressed DLD-1-CM-induced tube formation, migration, and adhesion on human umbilical vein endothelial cells. These effects were partly associated with reactive oxygen species generation by delta-T3. Western blot analysis revealed that the anti-angiogenic effect of delta-T3 is attributable to regulation of growth factor-dependent phosphatidylinositol-3 kinase (PI3K)/phosphoinositide-dependent protein kinase (PDK)/Akt signaling as well as to induction stress response in endothelial cells. Moreover, we conducted an in vivo mouse Matrigel plug angiogenesis assay, and found that delta-T3 (10-20 microg) exhibits dose-dependent inhibition of DLD-1-induced vessel formation. These results suggest that T3 has potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis.
Shibata
Akira
A
Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
Nakagawa
Kiyotaka
K
Sookwong
Phumon
P
Tsuzuki
Tsuyoshi
T
Oikawa
Shinichi
S
Miyazawa
Teruo
T
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007797:Laminin; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D003094:Collagen; D004338:Drug Combinations; D007797:Laminin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D014810:Vitamin E; C059485:matrigel; C082097:tocotrienol, delta