Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth.

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 levels 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.

• Authors: Lawrence Van Helleputte, Mandy Kater, Dana P Cook, Caroline Eykens, Elisabeth Rossaert, Wanda Haeck, Tom Jaspers, Natasja Geens, Pieter Vanden Berghe, Conny Gysemans, Chantal Mathieu, Wim Robberecht, Philip Van Damme, Guido Cavaletti, Matthew Jarpe, Ludo Van Den Bosch
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 111 Pg. 59-69 (03 2018) ISSN: 1095-953X [Electronic] United States
• PMID: 29197621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Neuroprotective Agents
• Tubulin
• Vincristine
• Histone Deacetylase 6

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacology)
• Axonal Transport (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Ganglia, Spinal (drug effects, metabolism)
• Histone Deacetylase 6 (antagonists & inhibitors, metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Male
• Mice, Inbred NOD
• Mice, SCID
• Microtubules (drug effects, metabolism)
• Mitochondria (drug effects, metabolism)
• Neoplasms (drug therapy, enzymology)
• Neuroprotective Agents (pharmacology)
• Peripheral Nervous System Diseases (chemically induced, drug therapy, enzymology)
• Tubulin (metabolism)
• Vincristine (adverse effects)