The antifungal drug itraconazole inhibits angiogenesis

Abstract

Angiogenesis, the formation of new blood vessels, is involved in numerous diseases such as tumor metastasis and diabetic retinopathy. In an effort to circumvent the high cost of de novo drug development we created and screened a library of 2,604 existing drugs for inhibition of human umbilical vein endothelial cell (HUVEC) proliferation. Among drugs that showed potent antiproliferative activity, one of the most promising and unexpected was itraconazole. The pill and i.v. formulations of itraconazole are supplied as a 1:1:1:1 mixture of four diastereomers. We synthesized the cis-4R and cis-4S pair and observe IC50 values for HUVEC proliferation of 1.1 ± 0.13 μM and 0.056 ± 0.01 μM, respectively, with the cis-4S diastereomer showing 88-fold selectivity over human fibroblasts (IC50 = 4.95 ± 0.28 μM). The cis-4S diastereomer potently inhibits HUVEC cell cycle progression at the G1/S transition. In humans itraconazole is administered intravenously at a dose of 105 mg/m2 twice daily. Mice treated with 112.5 mg/m2 itraconazole (37.5 mg/kg) i.p. once daily showed a 67.5% decrease in angiogenesis. These results suggest itraconazole warrants further investigation as an anti-angiogenic drug and highlight the promise of finding new pharmacologic activities amongst known drugs.