1. Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth
- Author
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Elisabeth Rossaert, Guido Cavaletti, Philip Van Damme, Tom Jaspers, Lawrence Van Helleputte, Wanda Haeck, Ludo Van Den Bosch, Dana P Cook, Pieter Vanden Berghe, Natasja Geens, Caroline Eykens, Matthew Jarpe, Chantal Mathieu, Wim Robberecht, Conny Gysemans, Mandy Kater, Van Helleputte, L, Kater, M, Cook, D, Eykens, C, Rossaert, E, Haeck, W, Jaspers, T, Geens, N, Vanden Berghe, P, Gysemans, C, Mathieu, C, Robberecht, W, Van Damme, P, Cavaletti, G, Jarpe, M, and Van Den Bosch, L
- Subjects
Male ,0301 basic medicine ,Vincristine ,medicine.medical_treatment ,Pain ,Antineoplastic Agents ,Microtubule ,Mice, SCID ,Pharmacology ,Histone Deacetylase 6 ,Microtubules ,Neuroprotection ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Dorsal root ganglion ,Mice, Inbred NOD ,Tubulin ,Ganglia, Spinal ,Neoplasms ,medicine ,Animals ,Chemotherapy ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cells, Cultured ,Axonal transport ,Cancer ,business.industry ,Neurotoxicity ,Peripheral Nervous System Diseases ,Acetylation ,HDAC6 ,medicine.disease ,Mitochondria ,Histone Deacetylase Inhibitors ,Disease Models, Animal ,Neuroprotective Agents ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Axoplasmic transport ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
As cancer is becoming more and more a chronic disease, a large proportion of patients is confronted with devastating side effects of certain anti-cancer drugs. The most common neurological complications are painful peripheral neuropathies. Chemotherapeutics that interfere with microtubules, including plant-derived vinca-alkaloids such as vincristine, can cause these chemotherapy-induced peripheral neuropathies (CIPN). Available treatments focus on symptom alleviation and pain reduction rather than prevention of the neuropathy. The aim of this study was to investigate the potential of specific histone deacetylase 6 (HDAC6) inhibitors as a preventive therapy for CIPN using multiple rodent models for vincristine-induced peripheral neuropathies (VIPN). HDAC6 inhibition increased the level of acetylated α-tubulin in tissues of rodents undergoing vincristine-based chemotherapy, which correlates to a reduced severity of the neurological symptoms, both at the electrophysiological and the behavioral level. Mechanistically, disturbances in axonal transport of mitochondria is considered as an important contributing factor in the pathophysiology of VIPN. As vincristine interferes with the polymerization of microtubules, we investigated whether disturbances in axonal transport could contribute to VIPN. We observed that increasing α-tubulin acetylation through HDAC6 inhibition restores vincristine-induced defects of axonal transport in cultured dorsal root ganglion neurons. Finally, we assured that HDAC6-inhibition offers neuroprotection without interfering with the anti-cancer efficacy of vincristine using a mouse model for acute lymphoblastic leukemia. Taken together, our results emphasize the therapeutic potential of HDAC6 inhibitors with beneficial effects both on vincristine-induced neurotoxicity, as well as on tumor proliferation. ispartof: Neurobiology of Disease vol:111 pages:59-69 ispartof: location:United States status: published
- Published
- 2018