Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1
Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1
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DOI：
10.1159/000076256
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发表时间：
2004-01-01
期刊：
影响因子：
3.1
通讯作者：
Lou, XE
中科院分区：
文献类型：
--
作者：
Chen, HH;Zhou, HJ;Lou, XE
青蒿琥酯（ART）是从植物黄花蒿中提取的青蒿素的半合成衍生物，是一种安全有效的抗疟疾药物。在本研究中，ART也被发现在体内和体外抑制血管生成。采用人卵巢癌HO-8910裸鼠移植瘤模型，采用免疫组化法检测微血管（CD 31）、血管内皮生长因子（VEGF）及VEGF受体KDR/flk-1的表达，评价其体内抗血管生成作用。药物治疗后肿瘤生长减少，微血管密度降低，对动物无明显毒性。ART还显著降低肿瘤细胞上VEGF的表达和内皮细胞以及肿瘤细胞上KDR/flk-1的表达。在血管生成模型上测试ART的体外作用，即人脐静脉内皮细胞（HUVEC）的增殖、迁移和管形成。结果表明，ART在0.5 ~ 50 μ mol/l范围内呈剂量依赖性地抑制血管生成。ART对人脐静脉内皮细胞增殖的抑制作用强于对人宫颈癌细胞、人子宫内膜癌细胞、NIH-3 T3成纤维细胞和人子宫内膜癌细胞的抑制作用，表明ART对人脐静脉内皮细胞具有选择性抑制作用。这些发现和已知的低毒性ART的线索，ART可能是一个有前途的血管生成抑制剂。版权所有（C）2004 S. Karger AG，巴塞尔。
Artesunate (ART) is a semi-synthetic derivative of artemisinin extracted from the plant Artemisia annua is a safe and effective antimalarial drug. In the present investigation, ART was found also to inhibit angiogenesis in vivo and in vitro. The anti-angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation and immunohistochemical stainings for microvessel (CD31), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. Tumor growth was decreased and microvessel density was reduced following drug treatment with no apparent toxicity to the animals. ART also remarkably lowered VEGF expression on tumor cells and KDR/flk-1 expression on endothelial cells as well as tumor cells. The in vitro effect of ART was tested on models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial cells ( HUVEC). The results showed that ART significantly inhibited angiogenesis in a dose-dependent form in the range of 0.5similar to50 mumol/l Additionally, the inhibitory effect of ART on HVUEC proliferation was stronger than that on Hela, JAR, HO-8910 cancer cells, NIH-3T3 fibroblast cells and human endometrial cells, indicating that ART was selectively against HUVEC. These findings and the known low toxicity of ART are clues that ART may be a promising angiogenesis inhibitor. Copyright (C) 2004 S. Karger AG, Basel.