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.

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

“…Consistent with the mitotoxicity theory of CIPN, swollen and vacuolated mitochondria appear in peripheral nerves and dorsal root ganglion (DRG) neuronal cell bodies in rodent models of peripheral neuropathy induced by paclitaxel, cisplatin, oxaliplatin, bortezomib, or vincristine . These abnormalities in mitochondrial morphology are accompanied by deficiencies in mitochondrial bioenergetics in DRG neurons and peripheral nerves in these models of CIPN . More specifically, impairments in mitochondrial basal respiration, maximal respiration capacity, and ATP production are observed …”

“…These abnormalities in mitochondrial morphology are accompanied by deficiencies in mitochondrial bioenergetics in DRG neurons and peripheral nerves in these models of CIPN . More specifically, impairments in mitochondrial basal respiration, maximal respiration capacity, and ATP production are observed …”

“…Chemotherapy‐induced mitochondrial dysfunction and the concomitant energy deficits in sensory neurons are believed to lead to the failure of these cells to sustain normal cellular activities, and ultimately to the symptoms of CIPN. For example, the formation of intraepidermal nerve fibers (IENFs) requires nerve fibers originating from subepidermal nerve fiber bundles to traverse the epidermal basal lamina and branch within the epidermis, which is a highly bioenergetically demanding process . In CIPN, the lack of a sufficient energy supply has been proposed to result in the inability of IENFs to sprout within the epidermis and thus to loss of IENFs, a clinical diagnostic marker of CIPN .…”

“…The neuroprotective effects of HDAC6 inhibitors in these models are associated with improved mitochondrial axonal transport and reduced oxidative damage . We recently demonstrated that HDAC6 inhibitors prevent cisplatin‐induced deficits in axonal mitochondrial transport in primary cultures of DRG neurons . In vivo, the coadministration of an HDAC6 inhibitor with cisplatin prevented cisplatin‐induced neuropathic pain.…”

Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain

“…injection of drugs and behavioral tests. The analgesic retigabine (#R-100, Alomone laboratory, Jerusalem, Israel) was administered intraperitoneally at a dose of 10 mg/kg in PBS 20 min before behavioral testing (Krukowski, et al 2017). …”