Repurposing the antihelmintic mebendazole as a hedgehog inhibitor Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Brain Neoplasms
  • Drug Repositioning
  • Hedgehog Proteins
  • Mebendazole
  • Medulloblastoma

abstract

  • 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.

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4297232

Digital Object Identifier (DOI)

  • 10.1158/1535-7163.MCT-14-0755-T

PubMed ID

  • 25376612

Additional Document Info

start page

  • 3

end page

  • 13

volume

  • 14

number

  • 1