RT Journal Article SR Electronic T1 Antiangiogenic and Vascular-Targeting Activity of the Microtubule-Destabilizing trans-Resveratrol Derivative 3,5,4′-Trimethoxystilbene JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1451 OP 1459 DO 10.1124/mol.104.009043 VO 67 IS 5 A1 Mirella Belleri A1 Domenico Ribatti A1 Stefania Nicoli A1 Franco Cotelli A1 Luca Forti A1 Vanio Vannini A1 Lucia Anna Stivala A1 Marco Presta YR 2005 UL http://molpharm.aspetjournals.org/content/67/5/1451.abstract AB Neovascularization plays an important role in neoplasia and angioproliferative diseases. Two major modalities have been developed so far to affect neovascularization: its prevention by antiangiogenic compounds, and immature vessel disruption by vascular-targeting agents. trans-Resveratrol, found in grapes and wine, exerts antioxidant, antineoplastic, and antiangiogenic activities. Here, among various synthetic trans-resveratrol derivatives tested, 3,5,4′-trimethoxystilbene was an antiangiogenic agent 30 to 100 times more potent than parent compound in inhibiting endothelial cell proliferation, sprouting, collagen gel invasion, and morphogenesis (ID50 = 0.3–3.0 μM). In addition, 3,5,4′-trimethoxystilbene acts as a vascular-targeting agent by causing microtubule disassembling and tubulin depolymerization and by impairing the repositioning of the microtubule organization center and the formation of membrane ruffles in migrating endothelial cells. In keeping with a vascular-targeting ability, 3,5,4′-trimethoxystilbene induced apoptosis only in subconfluent endothelial cells and apoptotic regression of immature vessels in the ex vivo rat aorta ring assay. In vivo, 3,5,4′-trimethoxystilbene caused the rapid stasis of blood flow and regression of intersegmental vessels in the trunk of zebrafish embryos. In addition, it inhibited blood vessel growth and caused the disappearance of pre-existing blood vessels in the area vasculosa of the chick embryo. In conclusion, 3,5,4′-trimethoxystilbene associates an antiangiogenic profile to a significant vascular-targeting activity.