Repurposing the antihelmintic mebendazole as a hedgehog inhibitor.
The hedgehog (Hh) signaling pathway is activated in many types of cancer and therefore presents an attractive target for new anticancer agents. Here, we show that mebendazole, a benzamidazole with a long history of safe use against nematode infestations and hydatid disease, potently inhibited Hh signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations. As an antiparasitic, mebendazole avidly binds nematode tubulin and causes inhibition of intestinal microtubule synthesis. In human cells, mebendazole suppressed the formation of the primary cilium, a microtubule-based organelle that functions as a signaling hub for Hh pathway activation. The inhibition of Hh signaling by mebendazole was unaffected by mutants in the gene that encodes human Smoothened (SMO), which are selectively propagated in cell clones that survive treatment with the Hh inhibitor vismodegib. Combination of vismodegib and mebendazole resulted in additive Hh signaling inhibition. Because mebendazole can be safely administered to adults and children at high doses over extended time periods, we propose that mebendazole could be rapidly repurposed and clinically tested as a prospective therapeutic agent for many tumors that are dependent on Hh signaling.
Department of Radiation Oncology and Molecular Radiation Sciences, The Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland.
Andrew R
AR
Larsen
Department of Neurosurgery, The Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland.
Ren-Yuan
RY
Bai
Department of Radiation Oncology and Molecular Radiation Sciences, The Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland.
Jon H
JH
Chung
Department of Neurosurgery, The Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland.
Alexandra
A
Borodovsky
Memorial Hospital Research Laboratories, Memorial Sloan Kettering Cancer Center, New York, New York.
Charles M
CM
Rudin
Department of Neurosurgery, The Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland. fbunz@jhmi.edu griggin1@jhmi.edu.
Gregory J
GJ
Riggins
Department of Radiation Oncology and Molecular Radiation Sciences, The Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland. fbunz@jhmi.edu griggin1@jhmi.edu.
Fred
F
Bunz
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058492:Drug Repositioning / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008463:Mebendazole / Q000008:administration & dosage* / Q000494:pharmacology; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D011725:Pyridines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D023041:Xenograft Model Antitumor Assays
D000813:Anilides; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D008463:Mebendazole