title: Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors.
abstract: The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
authors.forename: Michelle
authors.initials: M
authors.lastname: De Witt
authors.affiliation: Department of Neurosurgery, Northwell Health, Manhasset, NY 11030.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gamble
authors.affiliation: Division of Hematology/Oncology, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY 11040.
authors.forename: Derek
authors.initials: D
authors.lastname: Hanson
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
authors.forename: Daniel
authors.initials: D
authors.lastname: Markowitz
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Powell
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
authors.forename: Saleh
authors.initials: S
authors.lastname: Al Dimassi
authors.affiliation: Division of Hematology/Oncology, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY 11040.|Hofstra Northwell School of Medicine, Hempstead, NY 11549.
authors.forename: Mark
authors.initials: M
authors.lastname: Atlas
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.|Department of Neurosurgery, Northwell Health, Manhasset, NY 11030.|Hofstra Northwell School of Medicine, Hempstead, NY 11549.
authors.forename: John
authors.initials: J
authors.lastname: Boockvar
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.|Department of Radiation Oncology, Northwell Health, Manhasset, NY 11030.|Hofstra Northwell School of Medicine, Hempstead, NY 11549.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Ruggieri
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030.|Department of Neurosurgery, Northwell Health, Manhasset, NY 11030.|Hofstra Northwell School of Medicine, Hempstead, NY 11549.
authors.forename: Marc
authors.initials: M
authors.lastname: Symons
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D058492:Drug Repositioning; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced; D008463:Mebendazole / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000209:etiology; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D014750:Vincristine; D008463:Mebendazole
keywords: blood-brain barrier; brain tumor; glioma; mebendazole; neuropathy; vincristine