Author/Authors :
Kim، نويسنده , , Mingjian James and Tang، نويسنده , , Jean Y. and Gong، نويسنده , , Ruoyu and Kim، نويسنده , , Jynho and Lee، نويسنده , , John J. and Clemons، نويسنده , , Karl V. and Chong، نويسنده , , Curtis R. and Chang، نويسنده , , Kris S. and Fereshteh، نويسنده , , Mark and Gardner، نويسنده , , Dale and Reya، نويسنده , , Tannishtha and Liu، نويسنده , , Jun O. and Epstein، نويسنده , , Ervin H. and Stevens، نويسنده , , David A. and Beachy، نويسنده , , Philip A.، نويسنده ,
Abstract :
Summary
creen 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.
