Antimalarial dihydroartemisinin also inhibits angiogenesis
Antimalarial dihydroartemisinin also inhibits angiogenesis
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DOI：
10.1007/s00280-003-0751-4
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发表时间：
2004-05-01
影响因子：
3
通讯作者：
Wu, GD
中科院分区：
文献类型：
--
作者：
Chen, HH;Zhou, HJ;Wu, GD
双氢青蒿素是青蒿素衍生物的水溶性更强的代谢产物，是一种安全且最有效的青蒿素抗疟类似物。在本研究中，我们研究了双氢青蒿素的体外和体内抗血管生成活性，并研究了双氢青蒿素诱导的人脐静脉内皮细胞（HUVEC）细胞凋亡。双氢青蒿素显着减少 VEGF 与其 HUVEC 表面受体的结合。免疫细胞化学染色测定显示，双氢青蒿素治疗后 HUVEC 上两种主要 VEGF 受体 Flt-1 和 KDR/flk-1 的表达水平较低。在鸡绒毛尿囊膜（CAM）新生血管模型中评估体内抗血管生成活性。双氢青蒿素在低浓度（5-30 nmol/100 μl/卵）下显着抑制 CAM 血管生成。我们还定性和定量地研究了双氢青蒿素诱导 HUVEC 凋亡的情况。通过流式细胞术观察到双氢青蒿素诱导的 HUVEC 细胞凋亡呈剂量相关性（5-80 μM）和时间依赖性（6-36 小时）增加。我们的结果表明，双氢青蒿素诱导的抗血管生成作用可能是通过诱导细胞凋亡和抑制 VEGF 受体表达而发生的。这些发现和双氢青蒿素已知的低毒性表明它可能是一种有前途的候选血管生成抑制剂。
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.