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Kinesin-5 Blocker Monastrol Protects Against Bortezomib-Induced Peripheral Neurotoxicity

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Abstract

Neurotoxicity is a relevant side effect of bortezomib treatment. Previous reports have shown that the development of peripheral neuropathy caused by anti-neoplastic agents may be a result of reduced axonal transport. Based on evidence from prior studies that the kinesin-5 inhibitor monastrol enhances axonal transport and improves neuronal regeneration, we focused on the neuroprotective role of monastrol during the chemotherapeutic treatment with bortezomib. Prolonged treatment of C57BL/6 mice with bortezomib induced a length-dependent small-fiber neuropathy with axonal atrophy and loss of sensory nerve fibers. The administration of monastrol substantially alleviated morphological features of axonal injury and functional measures of sensory neuropathy. Cytotoxicity studies in leukemia and multiple myeloma cell lines showed no interference of monastrol with the cytostatic effects of bortezomib. Our data indicate that the novel approach of targeting microtubule turnover by monastrol provides protection against bortezomib-induced neurotoxicity. The favorable cytotoxic profile of monastrol makes it an interesting candidate as neuroprotective agent in combined chemotherapy regimens that warrants further consideration.

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Acknowledgements

Helmar Lehmann and Ilja Bobylev were supported by the Deutsche Krebshilfe (German Cancer Aid). The technical assistance of Claudia Drapatz (Department of Neurology, University Hospital of Cologne, Germany) and Petra Müller (Department of Anatomy I, Medical Faculty, University of Cologne, Germany) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Neurology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Ilja Bobylev, Ines Klein & Helmar C. Lehmann

  2. Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

    Ilja Bobylev, Ines Klein & Helmar C. Lehmann

  3. Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Düsseldorf, Germany

    Dominik Peters

  4. Experimental Tumor Research, Center for Tumor Biology and Immunology, Clinic for Hematology, Oncology and Immunology, Philipps University, Marburg, Germany

    Maulik Vyas & Elke Pogge von Strandmann

  5. Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany

    Mohammed Barham & Wolfram F. Neiss

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  1. Ilja Bobylev
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Correspondence to Helmar C. Lehmann.

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Bobylev, I., Peters, D., Vyas, M. et al. Kinesin-5 Blocker Monastrol Protects Against Bortezomib-Induced Peripheral Neurotoxicity. Neurotox Res 32, 555–562 (2017). https://doi.org/10.1007/s12640-017-9760-7

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  • DOI: https://doi.org/10.1007/s12640-017-9760-7

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