title: HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.
abstract: 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 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.
authors.affiliation: aDepartment of Symptom Research, Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA bAcetylon Pharmaceuticals Inc, Boston, MA, USA cCenter for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Krukowski
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Ma
authors.forename: Olga
authors.initials: O
authors.lastname: Golonzhka
authors.forename: Geoffroy O
authors.initials: GO
authors.lastname: Laumet
authors.forename: Tanuja
authors.initials: T
authors.lastname: Gutti
authors.forename: John H
authors.initials: JH
authors.lastname: van Duzer
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Jarpe
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002945:Cisplatin / Q000009:adverse effects*; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors*; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000139:chemically induced* / Q000175:diagnosis / Q000517:prevention & control*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000517:prevention & control*; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D011743:Pyrimidines; C545556:HDAC6 protein, rat; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D002945:Cisplatin; C572255:ricolinostat