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Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth

2010; Cell Press; Volume: 17; Issue: 4 Linguagem: Inglês

10.1016/j.ccr.2010.02.027

1878-3686

James Kim, Jean Y. Tang, Ruoyu Gong, Juyong Brian Kim, John J. Lee, Karl V. Clemons, Curtis R. Chong, Kris S. Chang, Mark Fereshteh, Dale R. Gardner, Tannishtha Reya, Jun O. Liu, Ervin H. Epstein, David A. Stevens, Philip A. Beachy,

Oral and gingival health research

In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.