Triptolide functions as a potent angiogenesis inhibitor
Triptolide functions as a potent angiogenesis inhibitor
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DOI：
10.1002/ijc.24694
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发表时间：
2010-01-01
影响因子：
6.4
通讯作者：
But, Paul Pui-Hay
中科院分区：
文献类型：
--
作者：
He, Ming-Fang;Huang, Yi-Hsien;But, Paul Pui-Hay
雷公藤内酯醇是中草药雷公藤的一种重要抗炎活性成分。F.（卫矛科）。它还具有强大的抗肿瘤活性。在这项研究中，我们表明，雷公藤内酯醇是一种血管生成抑制剂的基础上，各种血管生成试验。在体外试验中，IC 50为45 nM，这远低于给予雷公藤内酯醇的大鼠或人的血浆浓度。雷公藤提取物用于治疗炎症。当在体内给药时，雷公藤内酯醇在基质胶塞测定中在100 nM时有效地抑制血管生成。在小鼠肿瘤发生试验中，0.75 mg/kg/天的雷公藤内酯醇显著阻断肿瘤血管生成和肿瘤进展。半定量RT-PCR和western blot分析显示雷公藤内酯醇下调人脐静脉内皮细胞中促血管生成Tie 2和VEGFR-2的表达。虽然Tie 2抑制似乎是一个较晚的事件相比，VEGFR-2，Tie 2过表达显着减弱雷公藤甲素对内皮细胞增殖和网络形成的抑制作用。相比之下，Tie 2敲低模仿雷公藤甲素对内皮网络形成的抑制作用。雷公藤内酯醇的抗肿瘤作用部分是通过阻断2条内皮受体介导的信号通路来抑制肿瘤血管生成，雷公藤内酯醇可能是一种有前途的抗血管生成药物。
Triptolide is a key anti-inflammatory compound of the Chinese herbal medicine Tripterygium wilfordii Hook. f. (Celastraceae). It also possesses potent antitumor activity. In this study, we show that triptolide is an angiogenesis inhibitor based on various angiogenesis assays. The IC50 in in vitro assays was 45 nM, which was much lower than the plasma concentrations of triptolide in the rat or human administered with T. wilfordii extracts for treating inflammation. When dosed in vivo, triptolide potently inhibited angiogenesis at 100 nM in Matrigel plug assay. Triptolide at 0.75 mg/kg/day significantly blocked tumor angiogenesis and tumor progression in murine tumorigenesis assay. The underlying mechanism of triptolide correlated with downregulation of proangiogenic Tie2 and VEGFR-2 expression in human umbilical vein endothelial cell by semiquantitative RT-PCR and western blot analysis. Although Tie2 inhibition appeared to be a later event as compared with VEGFR-2, Tie2 overexpression significantly attenuated the inhibitory effect of triptolide on endothelial proliferation and network formation. By contrast, Tie2 knockdown mimicked the inhibitory effect of triptolide on endothelial network formation. Our findings suggest that antitumor action of triptolide is partly via inhibition of tumor angiogenesis by blocking 2 endothelial receptor-mediated signaling pathways, and triptolide can be a promising antiangiogenic agent.