Abstract
The microtubule inhibitor vincristine is currently used to treat a number of brain tumors, including newly diagnosed diffuse low-grade and anaplastic glioma. Vincristine however does not penetrate well into brain tumor tissue and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, an anti-helminthic with an excellent safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma (Bai R-Y et al, 2011 and Bai R-Y et al, 2014). In addition, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain (Bai R-Y et al, 2015). Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this microtubule inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, metaphase arrest and microtubule polymerization and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the 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 indeed is caused by inhibiting microtubule formation. We also have compared the therapeutic efficacies of mebendazole and vincristine against GL261 orthotopic tumors at their respective maximum tolerated doses (respectively 100 mg/kg/day and 1 mg/kg/week). We found that mebendazole showed a 61% increase in animal survival time, whereas vincristine failed to show any efficacy. However, we did observe significant neuropathy (as measured by sensory allodynia) induced by mebendazole treatment, similar to that caused by vincristine. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.
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