Inhibition of angiogenesis by the antifungal drug itraconazole
Inhibition of angiogenesis by the antifungal drug itraconazole
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DOI：
10.1021/cb600362d
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发表时间：
2007-04-01
影响因子：
4
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Chong, Curtis R.;Xu, Jing;Liu, Jun O.
血管生成，即新血管的形成，与许多重要的人类疾病有关，包括癌症、糖尿病视网膜病变和类风湿性关节炎。为了确定临床上有用的血管生成抑制剂，我们收集并筛选了一个主要由美国食品药品监督管理局批准的药物组成的文库，以寻找抑制人类内皮细胞增殖的药物。最有前景且意想不到的命中药物之一是伊曲康唑，一种已知的抗真菌药物。伊曲康唑在体外抑制内皮细胞周期在G1期的进展，并在体内阻断血管内皮生长因子/碱性成纤维细胞生长因子依赖的血管生成。在试图阐明伊曲康唑作用机制的过程中，我们发现人类羊毛甾醇14 - 去甲基酶（14DM）对内皮细胞增殖至关重要，并且可能部分介导伊曲康唑对内皮细胞的抑制作用。总之，这些发现表明伊曲康唑有作为一种抗血管生成药物的潜力，并且羊毛甾醇14DM是发现新的血管生成抑制剂的一个有希望的新靶点。
Angiogenesis, the formation of new blood vessels, is implicated in a number of important human diseases, including cancer, diabetic retinopathy, and rheumatoid arthritis. To identify clinically useful angiogenesis inhibitors, we assembled and screened a library of mostly Food and Drug Administration-approved drugs for inhibitors of human endothelial cell proliferation. One of the most promising and unexpected hits was itraconazole, a known antifungal drug. Itraconazole inhibits endothelial cell cycle progression at the G1 phase in vitro and blocks vascular endothelial growth factor/basic fibroblast growth factor-dependent angiogenesis in vivo. In attempts to delineate the mechanism of action of itraconazole, we found that human lanosterol 14-demethylase (14DM) is essential for endothelial cell proliferation and may partially mediate the inhibition of endothelial cells by itraconazole. Together, these findings suggest that itraconazole has the potential to serve as an antiangiogenic drug and that lanosterol 14DM is a promising new target for discovering new angiogenesis inhibitors.