title: Antimalarial dihydroartemisinin also inhibits angiogenesis.
abstract: Dihydroartemisinin, a more water-soluble metabolite of artemisinin derivatives, is a safe and most effective antimalarial analog of artemisinin. In the present study, we investigated the antiangiogenic activity of dihydroartemisinin in vitro and in vivo, and investigated dihydroartemisinin-induced apoptosis in human umbilical vein endothelial cells (HUVEC). Dihydroartemisinin markedly reduced VEGF binding to its receptors on the surface of HUVEC. The expression levels of two major VEGF receptors, Flt-1 and KDR/flk-1, on HUVEC were lower following dihydroartemisinin treatment as shown by an immunocytochemical staining assay. The in vivo antiangiogenic activity was evaluated in the model of chicken chorioallantoic membrane (CAM) neovascularization. Dihydroartemisinin significantly inhibited CAM angiogenesis at low concentrations (5-30 nmol/100 microl per egg). We also investigated both qualitatively and quantitatively the induction of HUVEC apoptosis by dihydroartemisinin. A dose-related (5-80 microM) and time-dependent (6-36 h) increase in dihydroartemisinin-induced HUVEC apoptosis was observed by flow cytometry. Our results suggest that the antiangiogenic effect induced by dihydroartemisinin might occur by induction of cellular apoptosis and inhibition of expression of VEGF receptors. These findings and the known low toxicity of dihydroartemisinin indicate that it might be a promising candidate angiogenesis inhibitor.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Chen
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Zhou
authors.forename: Wei-Qin
authors.initials: WQ
authors.lastname: Wang
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Wu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012717:Sesquiterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; C039060:artenimol; D040262:Receptors, Vascular Endothelial Growth Factor