Abstract
Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients’ daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control.
Highlights
The success of cancer treatment has increased dramatically over the past decade, with the survivor population reaching 15.5 million in the US alone and 28 million worldwide in 2016 [14, 22]
Our result suggests that penetration of the inhibitor into the brain is likely required, as the non-brain-penetrating histone deacetylase 6 (HDAC6) inhibitor ACY-1215 had no effect on cognitive function at a dosing schedule that reversed cisplatin-induced peripheral neuropathy [31]
We demonstrate that deacetylation of α-tubulin and hyperphosphorylation of tau were part of the mechanism contributing to cisplatin-induced cognitive impairment, and that HDAC6 inhibition reversed these pathological changes as well
Summary
The success of cancer treatment has increased dramatically over the past decade, with the survivor population reaching 15.5 million in the US alone and 28 million worldwide in 2016 [14, 22]. An absolute requirement for the treatment of CICI would be to exclusively use agents that do not interfere with, and preferably even enhance. Ma et al Acta Neuropathologica Communications (2018) 6:103 tumor control. In this regard, agents targeting histone deacetylase 6 (HDAC6) are promising candidates to fill this void. Inhibitors of HDAC6 display anti-tumor activity in various cancer models; HDAC6 inhibition is being considered as an add-on treatment to inhibit tumor growth [1, 2, 24, 46]. One of the HDAC6 inhibitors, ACY-1215 (ricolinostat), is currently in multiple clinical trials for evaluation of its anti-tumor activity (NCT01997840, NCT02091063, NCT02632071, NCT01583283, NCT02189343, NCT02787369). It has already been shown to be safe, well-tolerated, and active in enhancing the efficacy of the combination of bortezomib and dexamethasone for multiple myeloma in a Phase II clinical trial (NCT01323751) [46]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
