Mebendazole and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma

Abstract

Purpose Meningiomas are a frequent tumor of the central nervous system. Although mostly benign, approximately 5% present as atypical or malignant tumors. Treatments for atypical meningiomas include gross total resection and radiotherapy, but about 33% of patients have recurrent tumors, sometimes as a higher grade. Recently, the brain penetrant anthelmintic drug, mebendazole, has shown promise as an anticancer agent in rodent models of glioblastoma and medulloblastoma. Methods The half maximal inhibitory concentration (IC50), effect on; colony formation, cell proliferation, and caspase-3/7 markers of apoptosis of mebendazole with and without radiation was measured in vitro. Mice intracranially implanted with KT21MG1 human meningioma were administered mebendazole alone or in combination with radiation. Survival benefit was evaluated, while tumors were investigated by immunohistochemical staining for apoptosis, cell proliferation, and vascular density. Results In vitro experiments on meningioma cell lines showed the IC50 for mebendazole in the range of 0.26 to 0.42 μM. Mebendazole alone induced cytotoxicity, however the combination had a greater reduction in colony formation and resulted in higher levels of cleaved caspase-3. The in vivo study showed both, mebendazole alone and the combination, to have a survival benefit with an increase in apoptosis, and decreases in tumor cell and vascular proliferation. Conclusion These preclinical findings indicate that mebendazole alone or in combination with radiation can be considered for the treatment of malignant meningioma. The mechanism of action for this combination may include an increase in apoptosis, a reduction in proliferation and angiogenesis, or a combination of these effects.

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

“…Supplementary Table 1 ( 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 ) summarizes the antitumorigenicity of benzimidazole anthelmintics on cancer cell lines. Benzimidazole anthelmintics inhibit the progression of cancer through a variety of mechanisms.…”

“…We summarized the antitumorigenicity of benzimidazole anthelmintics in animal tumor models ( Supplementary Table 2 ) ( 4 8 11 12 13 14 15 16 17 20 27 28 29 30 34 35 36 37 39 45 47 51 52 54 55 56 57 61 63 64 65 66 69 70 71 74 75 76 78 79 80 92 93 94 ). Benzimidazole anthelmintics have been shown to inhibit the tumor growth in animals, which have been well-tolerated without significant side effects during the experimental period.…”

Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

“…Meningioma is a usually benign tumor of the central nervous system, but approximately 5% of the cases are represented by a malignant variant characterized by dismal prognosis [54]. Skibinski et al described the antitumoral effect of MBZ on malignant meningioma combined with IR [55]. In vitro, MBZ showed antiproliferative effects on several meningioma lines with IC 50s in the 0.26–0.42 μM range.…”

In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

“…Our methodology thus identified 17 novel putative targets of MBZ. We also observed that 12 of the 21 predicted targets are significantly overexpressed in GBM as compared to normal brain tissue, which may explain why MBZ is particularly effective against brain tumors [11,13,14,17,31].…”