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.