Antitumor activities of synthetic and natural stilbenes through antiangiogenic action.
We reported that the antitumor and antimetastatic actions of resveratrol might be due to the inhibition of tumor-induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, we examined the antiangiogenic effects of 21 synthetic and/or natural stilbenes. Among these 21 stilbenes, 2,3-, 3,4-, and 4,4'-dihydroxystilbene inhibited the pro-matrix metalloproteinase (pro-MMP)-9 production in colon 26 cells at 5-25 microM, vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) migration at 10 and 25 microM, and VEGF-induced angiogenesis at 5-50 microM. Resvertarol inhibited the pro-MMP-9 production and VEGF-induced angiogenesis at 25 or 50 microM. Thus, the inhibition of pro-MMP-9 production in colon 26 cells and VEGF-induced angiogenesis by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, intraperitoneal injection) inhibited the tumor-induced neovascularization in colon 26-packed chamber-bearing mice and the tumor growth in colon 26-bearing mice. Furthermore, the three dihydroxystilbenes inhibited VEGF-induced VEGFR-2 phosphorylation. On the other hand, the three dihydroxystilbenes had no effect on VEGFR-1 and-2 expression, and VEGF-induced VEGFR-1 phosphorylation in HUVECs. These findings suggest that the inhibition of tumor-induced neovascularization by these three dihydroxystilbenes may be due to the inhibition of VEGF-induced endothelial cell migration and VEGF-induced angiogenesis through the inhibition of VEGF-induced VEGFR-2 phosphorylation in endothelial cells and pro-MMP-9 expression in colon 26 cells.
Kimura
Yoshiyuki
Y
Division of Biochemical Pharmacology, Department of Basic Medical Research, Graduate School of Medicine, Ehime University, Toon City, Ehime, Japan. yokim@m.ehime-u.ac.jp
Sumiyoshi
Maho
M
Baba
Kimiye
K
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D003470:Culture Media / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D003470:Culture Media; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9