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.

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

“…Clinical trials involving drug repurposing are summarized in Supporting Information Table S1. Mebendazole has shown antitumor activity against HGG in preclinical studies by virtue of a mechanism of action analogous to that of vincristine and is currently being tested in a phase I trial for relapsed/refractory brain tumors (NCT02644291). Additionally, the HIT‐HGG‐2013 trial is evaluating the use of chloroquine, as autophagy inhibitor, in addition to temozolomide and radiotherapy in one of its experimental arms (NCT03243461).…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Clinical trials employing mebendazole for the treatment of high-grade glioma patients which receive temozolomide and for recurrent/progressive pediatric brain tumors are in the recruiting phase. Furthermore, this drug is tested preclinically as replacement for vincristine for the treatment of brain tumors [32]. Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33].…”

“…Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33]. Colon Cancer [52] Breast Cancer Triple [29] Breast Cancer [53] Adrenocortical Cancer [19] Adrenocortical Cancer [39] Leukemia/Myeloma [25] Leukemia/Myeloma [34] Leukemia/Myeloma [59,64] NSCLC [20] NSCLC [36] Lung Cancer CSC [57] Cell Lines [9] Cancer stem cells [46] Cancer [61] Gastric Cancer [22] Osteosarcoma [37] Medulloblastoma [23] Prostate Cancer [36] Melanoma [21,29] Ovarian Cancer/ TICs [41 -44] Ovarian cancer [62] Breast CSC-like Cells [26] Breast CSC-like Cells [40] Breast CSC-like Cells [56] Glioblastoma [24,32] Glioblastoma [33] Glioblastoma CD133 + [60] This table lists reports on investigations employing mebendazole, niclosamide and pyrvinium (pamoate) as anticancer agents against cell lines or in experimental animal models.…”

“…For the anticancer activity of mebendazole impairment of the organization of tubulin was identified as main intracellular effect in lung cancer, gastric cancer, leukemia and brain tumors [9,20,22,25,32]. Cytotoxicity was enhanced by alterations of the regulators of apoptosis, such as Bcl2/XIAP, in melanoma, lung cancer and adrenocortical carcinoma [9,19,21,67].…”

“…Correspondingly, the in vivo growth of hedgehog-dependent medulloblastoma was inhibited by orally administered mebendazole. Targets Tubulin NSCLC [20], lung cancer [9], gastric carcinoma [22], leukemia [25], brain tumor [32] Apoptosis Adrenocortical CA [19], BCL2/XIAP melanoma [21,62], BCL-2 lung cancer [9].…”