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

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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 0.26–0.42 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.

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Funding

This work was funded by grants from the National Institutes of Health (R21CA195149 and RO1CA190223), generous gifts from Peter Jennison, Leonard and Phyllis Attman, and through support to GJR via the Irving J. Sherman M.D. Research Professorship.

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Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Christine G. Skibinski, Tara Williamson & Gregory J. Riggins

Authors
  1. Christine G. Skibinski
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  2. Tara Williamson
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  3. Gregory J. Riggins
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Contributions

CGS performed all the experiments assisted by TW for animal experiments. CGS and GJR created the study design. GJR originated the study hypothesis.

Corresponding author

Correspondence to Gregory J. Riggins.

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Conflict of interest

Dr. Riggins is a founder of and holds equity in Benizole Therapeutics PBC. The results of the study discussed in this publication could affect the value of Benizole. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. GJR has a financial interest in Benizole Therapeutics, PBC and in mebendazole related intellectual property managed by Johns Hopkins University.

Ethical approval

Rodent experiments were performed using a protocol approved by the Johns Hopkins University Institutional Animal Care and Use Committee.

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Skibinski, C.G., Williamson, T. & Riggins, G.J. Mebendazole and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma. J Neurooncol 140, 529–538 (2018). https://doi.org/10.1007/s11060-018-03009-7

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  • DOI: https://doi.org/10.1007/s11060-018-03009-7

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