Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway.
Costunolide (CT), a sesquiterpene lactone constituent isolated from Saussurea lappa (Compositae), exerted an antiangiogenic effect. CT selectively inhibited the endothelial cell proliferation induced by vascular endothelial growth factor (VEGF). Further, CT was also found to inhibit the VEGF-induced chemotaxis of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. From these results, we hypothesized that CT might inhibit angiogenesis by blocking the angiogenic factor signaling pathway. VEGF interacts with its cognate receptors, KDR/Flk-1 and Flt-1, and exerts its angiogenic effect. CT inhibited the autophosphorylation of KDR/Flk-1 without affecting that of Flt-1. Moreover, administration of CT reduced VEGF-induced neovascularization in a mouse corneal micropocket assay. These results suggest that CT may prove useful for the development of a novel angiogenesis inhibitor.
D016475:3T3 Cells; D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002633:Chemotaxis; D016510:Corneal Neovascularization / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D030441:Saussurea / Q000737:chemistry*; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors; D007783:Lactones
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D042442:Vascular Endothelial Growth Factors; C002602:costunolide; D007783:Lactones