title: Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth.
abstract: 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.
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kim
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Gong
authors.forename: Jynho
authors.initials: J
authors.lastname: Kim
authors.forename: John J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Karl V
authors.initials: KV
authors.lastname: Clemons
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Chong
authors.forename: Kris S
authors.initials: KS
authors.lastname: Chang
authors.forename: Mark
authors.initials: M
authors.lastname: Fereshteh
authors.forename: Dale
authors.initials: D
authors.lastname: Gardner
authors.forename: Tannishtha
authors.initials: T
authors.lastname: Reya
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Ervin H
authors.initials: EH
authors.lastname: Epstein
authors.forename: David A
authors.initials: DA
authors.lastname: Stevens
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D003505:Cyclodextrins / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D003505:Cyclodextrins; D053823:Hedgehog Proteins; D008077:Lipoproteins, LDL; D017964:Itraconazole
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