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, 23, 50-56

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

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Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

Michelle De Witt et al. Mol Med.

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.

Keywords: blood-brain barrier; brain tumor; glioma; mebendazole; neuropathy; vincristine.

Conflict of interest statement

DISCLOSURE

The authors declare they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.

Figures

Figure 1.
Figure 1.
Mebendazole and vincristine have similar inhibitory effects on cell viability and microtubule polymerization. (A,B) Western blots illustrating microtubule depolymerization caused by incubation of GL261 cells with the indicated concentrations of mebendazole (MBZ) and vincristine (VCR). Cells were processed, and polymerized (P) and soluble (S) tubulin were separated by centrifugation as described in Materials and Methods. (C,D) Concentration dependence of microtubule polymerization and cell viability: (C) mebendazole, (D) vincristine. Microtubule polymerization was determined as the percentage of polymerized tubulin over total tubulin. Determination of cell viability was performed as described in Materials and Methods. Data shown were normalized to vehicle control values and represent the mean ± SEM of three and at least eight independent experiments for the microtubule polymerization and cell viability experiments, respectively.
Figure 2.
Figure 2.
Mebendazole and vincristine induce metaphase arrest with a similar concentration dependence as that of cell viability. (A) Time dependence of mebendazole-induced metaphase arrest. Mebendazole concentration was 500 nM. Data shown represent the mean ± SEM of three independent experiments. (B,C) Concentration dependence of metaphase arrest: (B) mebendazole, (C) vincristine. Data shown represent the mean ± SEM of three independent experiments.
Figure 3.
Figure 3.
Mebendazole, but not vincristine, promotes the survival of glioma-bearing mice. Kaplan-Meier survival curves of mice implanted with GL261 glioma cells and treated with different doses of mebendazole and vincristine. Group sizes of the respective groups are 11–12.
Figure 4.
Figure 4.
Drug-induced toxicities. (A) Peripheral neuropathy in mebendazole- and vincristine-treated mice. Shown are the mean ± SEM (n = 12) of footpad sensitivity measurements using von Frey filaments on d 6 after treatment initiation. (B) Animal weights before and during treatment. Data points represent the weight averages for each group ± SEM (n = 12).

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