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.
Highlights
The microtubule polymerization inhibitor vincristine has a broad spectrum of use in cancer chemotherapy, for both hematological malignancies and solid tumors
Because of its large size (MW 825 daltons) and its susceptibility to transport by Mrp1 and Pgp, vincristine has poor blood-brain barrier (BBB) penetrance [4,5]
We examined the mechanisms of tumor cell killing of mebendazole in detail, motivated by the possibility that mebendazole may be able to serve as a safer and more effective replacement for vincristine for the treatment of brain tumors
Summary
The microtubule polymerization inhibitor vincristine has a broad spectrum of use in cancer chemotherapy, for both hematological malignancies and solid tumors. Vincristine is used in the treatment of a variety of central nervous system (CNS). Along with procarbazine and lomustine (CCNU), it constitutes the PCV regimen, which is currently considered standard of care for newly diagnosed patients with 1p/19q co-deleted anaplastic oligodendroglioma [1,2] and adult patients with low-grade glioma [3]. Because of its large size (MW 825 daltons) and its susceptibility to transport by Mrp and Pgp, vincristine has poor blood-brain barrier (BBB) penetrance [4,5]. Its use for the treatment of CNS tumors has been questioned [4,6]. The peripheral neuropathies resulting from its use can be debilitating and permanent, often halting use of the drug [7,8]
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