HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

作者：Karen Krukowski, Jiacheng Ma, Olga Golonzhka, Geoffroy Laumet, T. Gutti, John H. van Duzer, Ralph Mazitschek, Matthew Jarpe, Cobi J. Heijnen, Annemieke Kavelaars · 发表于：Pain · 年份：2017 · DOI：10.1097/j.pain.0000000000000893 · 被引用次数：189 · 研究领域：Cancer Treatment and Pharmacology、Histone Deacetylase Inhibitors Research、Multiple Myeloma Research and Treatments

Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 complete...