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HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy

Krukowski, Karena; Ma, Jiachenga; Golonzhka, Olgab; Laumet, Geoffroy O.a; Gutti, Tanujaa; van Duzer, John H.b; Mazitschek, Ralphc; Jarpe, Matthew B.b; Heijnen, Cobi J.a; Kavelaars, Annemiekea,*

doi: 10.1097/j.pain.0000000000000893
Research Paper

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.

Inhibition of HDAC6 prevents and reverses the existing cisplatin-induced CIPN by relieving deficits in mitochondrial bioenergetics in sensory nerves and reversing intraepidermal nerve fiber loss.

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

Corresponding author. Address: Department of Symptom Research, Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 384, Houston, TX 77030, USA. Tel.: (713) 794-5297. E-mail address: akavelaars@mdanderson.org (A. Kavelaars).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received January 17, 2017

Received in revised form February 16, 2017

Accepted February 24, 2017

© 2017 International Association for the Study of Pain
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