Protective effect of new histone deacetylase 6 inhibitors in a cisplatin-induced peripheral neurotoxicity murine model

Introduction: Histone deacetylase 6 (HDAC6) inhibitors have shown effectiveness in preclinical models of chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of various antineoplastic drugs, with no available preventive or therapeutic treatments. This study presents in vivo results for ITF6464 and ITF6475, 2 HDAC6 inhibitors featuring a difluoromethyloxadiazole (DFMO), zinc-binding group ensuring selectivity for HDAC6. Objectives: This study investigated the potential effect of 2 new selective DFMO HDAC6 inhibitors in preventive and curative settings in a well-established CIPN model. Methods: The effectiveness of treatments was evaluated by dynamic test and histological analysis on dorsal root ganglia (DRG) and skin biopsy. The acetylation of tubulin was also investigated in sciatic nerve by western blot. Results: ITF6464 and ITF6475 administered at 12.5 mg/kg dose prevented cisplatin-induced mechanical allodynia (*** P < 0.001 and ** P < 0.01, respectively). Histologically, both ITF6464 and ITF6475 at all doses prevented damage in DRGs. ITF6464 at 6 mg/kg and ITF6475 at 1 mg/kg protected intraepidermal nerve fibers (IENF) from cisplatin-induced damage (* P < 0.05). After 2 cisplatin cycles, ITF6475 12.5 mg/kg was effective in reverting mechanical allodynia (*** P < 0.001). ITF6475 reverted cisplatin-induced damage in DRGs and, at the highest dose, also reverted IENF damage ( ○○ P < 0.01). Cisplatin induced a reduction in acetylated tubulin in the sciatic nerve of mice, and ITF6464 and ITF6475 at 12.5 mg/kg dose were able to significantly revert this condition. Conclusions: These studies highlight the potential of the new selective HDAC6 inhibitors ITF6464 and ITF6475 as promising treatments for CIPN.