αvβ3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers

Angiogenesis is target for antineoplastic and chemopreventive therapies. The natural phytoalexin resveratrol is found in grapes and red wine as cis and trans stateoisomers. trans-Resveratrol shows antiangiogenic activity, but its mechanism of action is not fully elucidated. Recently, trans-resveratrol has been shown to interact with the beta(3) integrin subunit, raising the possibility that inhibition of endothelial alpha(v)beta(3) integrin function may concur to its angiosuppressive activity. To get novel insights about the antiangiogenic activity of resveratrol, we compared cis- and trans-Resveratrol stereoisomers for their effect on the angiogenesis process and endothelial alpha(v)beta(3) integrin function. trans-Resveratrol inhibits endothelial cell proliferation and the repair of mechanically wounded endothelial cell monolayers. Also, it prevents endothelial cell sprouting in fibrin gel, collagen gel invasion, and morphogenesis an Matrigel. In vivo, trans-resveratrol inhibits vascularization of the chick embryo area vasculosa and murine melanoma B16 tumor growth and neovascularization. In all the assays, cis-resveratrol exerts a limited, if any, effect. In keeping with these observations, transresveratrol, but not cis-resveratrol, inhibits alpha(v)beta(3) integrin-dependent endothelial cell adhesion and the recruitment of enhanced green fluorescent protein-tagged 3 integrin in focal adhesion contacts. In conclusion, stereoisomery affects the antiangiogenic activity of resveratiol, the trans isomer being significantly more potent than the cis isoform. The different antiangiogenic potential of resveratrol stereoisomers is related, at least in part, to their different capacity to affect alpha(v)beta(3) integrin function. This may have profound implications for the design of synthetic antiangiogenic/angiopreventive phytoalexin derivatives. [Mol Cancer Ther 2008;7(12):3761-70]