青蒿琥酯和体内主要代谢物二氢青蒿素的抗新生血管生成作用研究进展

Inhibitory effects of artesunate and dihydroartemisinin on angiogenesis

目的:研究青蒿酯琥和二氢青蒿素对血管生成的抑制作用.方法:采用人卵巢癌裸鼠移植瘤模型。假孕大鼠蜕膜瘤模型,鸡胚尿囊膜血管生成模型研究药物的体内抗血管生成作用.用人脐静脉内皮细胞(HUVEC)的生长,迁移及小管形成等实验方法研究药物的体外抗血管生成作用以及诱导HUVEC凋亡的作用.结果:在整体实验中,50mg·kg-1·d-1青蒿琥酯即可明显减少肿瘤的血管生成,抑制肿瘤生长;40mg·kg-1·d-1青蒿琥酯即可明显减少假孕大鼠蜕膜组织和骨髓血管生成.免疫组化结果表明,青蒿琥酯可以抑制VEGF和KDR/flk-1在肿瘤组织中的表达,对假孕大鼠蜕膜和骨髓组织中VEGF也同样受到抑制.青蒿琥酯在15μg/胚时对正常鸡胚尿囊膜血管生成有抑制作用,在7.5μg/胚时对种植肿瘤细胞的鸡胚尿囊膜血管生成就有抑制作用.在体外实验中,青蒿琥酯和二氢青蒿素均对HUVEC的增殖,迁移和小管形成有显著的抑制作用,二氢青蒿素的作用强度更大;青蒿琥酯和二氢青蒿素抑制HUVEC生长的IC50值分别为(29.7±3.2)μmol/L和(21.8±3.8)μmol·L-1.结论:青蒿琥酯和二氢青蒿素有抗血管生成作用,结合其低毒、副作用少的优点,表明这类药物在抗血管生成中有潜在的应用价值.

Aim:To investigate the inhibitory effects of artesunate and dihydroartemisinin on angiogenesis. Methods:The in vitro anti-angiogenic effect of artesunate and dihydroartemisinin was tested on models of angiogenesis: proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells, and apoptosis of HUVECS; The anti - angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation , deciduoma and marrow, immunohistochemical stainings for microvessel (CD31,Ⅷ Factor), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. Results:Artesunate and dihydroartemisinin significantly inhibited angiogenisis in a concentration-dependent form in range of 0.5~50μmol·.L-1.The IC50 of artesunate and dihydroartemisinin for HUVE cells was (29.7±3.2)μmol/L and (21.8±3.8μmol·L-1 respectively, and induced HUVECS apoptosis. Growth of xenograft tumor was decreased and microvessel density was reduced following drug - treatment with no apparent toxicity to the animals. Artesunate also remarkably lowered VEGF expression on tumor cells and KDR/flk -1 expression on endothelial cells as well as deciduoma and marrow. Conclusion; Artesunate and dihydroartemisinin was shown to inhibit angiogenesis in vitro and in vivo. These findings together with the known low toxicity of artesunate and dihydroartemisinin are clues that both may be promising angiogenesis inhibitors.