Journal
NEUROBIOLOGY OF DISEASE
Volume 111, Issue -, Pages 59-69Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2017.11.011
Keywords
Cancer; Chemotherapy; Axonal transport; Pain; Acetylation; Microtubules
Categories
Funding
- Fund for Scientific Research Flanders [FWO G.0920.15]
- Belgian government (Interuniversity Attraction Poles of the Belgian Federal Science Policy Office) [P7/16]
- Association Belge contre les Maladies neuro-Musculaires (ABMM)
- Muscular Dystrophy Association [MDA295317]
- European Community's Health Seventh Framework Programme [259867]
- NIH [NS079183]
- 'Opening the Future' Fund (KU Leuven)
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- European Research Council under the European's Seventh Framework Programme/ ERC [340429]
- 'Agency for Innovation by Science and Technology in Flanders' (IWT-Vlaanderen)
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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 vincaalkaloids 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 levels of acetylated a-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 a-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.
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