Antimalarial dihydroartemisinin also inhibits angiogenesis

被引:135
作者
Chen, HH
Zhou, HJ [1 ]
Wang, WQ
Wu, GD
机构
[1] Zhejiang Univ, Coll Pharmaceut Sci, Dept Pharmacol & Toxicol, Hangzhou 310031, Peoples R China
[2] Zhejiang Univ, Affiliated Hosp 1, Coll Med, Dept Clin Pharmacol, Hangzhou 310031, Peoples R China
关键词
dihydroartemisinin; anglogenesis; vascular endothelial growth factor (VEGF); VEGF receptor; apoptosis;
D O I
10.1007/s00280-003-0751-4
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 mul per egg). We also investigated both qualitatively and quantitatively the induction of HUVEC apoptosis by dihydroartemisinin. A dose-related (5-80 muM) 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.
引用
收藏
页码:423 / 432
页数:10
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