title: Inhibition of angiogenesis by the antifungal drug itraconazole.
abstract: 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 14alpha-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.
authors: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Curtis R
authors: CR
authors: Chong
authors: Jing
authors: J
authors: Xu
authors: Jun
authors: J
authors: Lu
authors: Shridhar
authors: S
authors: Bhat
authors: David J
authors: DJ
authors: Sullivan
authors: Jun O
authors: JO
authors: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D058886:Sterol 14-Demethylase
chemical_list: D020533:Angiogenesis Inhibitors; D000935:Antifungal Agents; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D017964:Itraconazole; D010088:Oxidoreductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase