Journal Article

ITF6475, a New Histone Deacetylase 6 Inhibitor, Prevents Painful Neuropathy Induced by Paclitaxel

Crippa, Luca, Alberti, Paola, Cavaletti, Guido, Meregalli, Cristina, Vergani, Barbara, Chiorazzi, Alessia, Fermi, Silvia, Steinkühler, Christian, Marmiroli, Paola, Canta, Annalisa, Pozzi, Eleonora, Licandro, Simonetta Andrea, Segmani, Ibtihal, Carozzi, Valentina, Scuteri, Arianna

2025

Overview

Chemotherapy-induced peripheral neuropathy remains a significant side effect of cancer treatment, often requiring dose reductions or even discontinuation of therapy. Paclitaxel (PTX), a widely used chemotherapeutic agent for solid tumors, is particularly neurotoxic, and no effective treatment exists for paclitaxel-induced peripheral neuropathy (PIPN). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, including transcription factors and cytoskeletal components. This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent PIPN and compares its effects with ricolinostat, a well-established HDAC6 inhibitor previously studied in cisplatin-induced neuropathy models. Female C57BL/6 mice received PTX vehicle (VEH) or PTX (70 mg/kg intravenously, once per week for four weeks), and the remaining four groups received PTX with co-treatment of either ricolinostat (50 mg/kg orally, daily) or ITF6475 (1, 6, or 12.5 mg/kg orally, daily). Neurophysiological assessments at the end of treatment showed a significant reduction in caudal sensory nerve action potential amplitude across all PTX-treated groups compared to the VEH group. At the same time, PTX treatment led to the development of mechanical allodynia. However, co-treatment with the HDAC6 inhibitor prevented significant differences compared to the VEH group. PTX-induced reduction in intraepidermal nerve fiber density was significantly prevented in the PTX + ITF6475 (1 mg/kg) group, and PTX-induced increase in neurofilament light levels was reduced in all ITF6475 co-treated groups. These findings support the potential of ITF6475 in preventing small fiber damage in a severe, chronic PIPN model.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Action potential / Analysis / Animal models / Cancer / Cancer therapies / Cell cycle / Chemotherapy / Cisplatin / Cytoskeleton / Damage prevention / Drug dosages / Ethylenediaminetetraacetic acid / Histone deacetylase / histone deacetylase 6 / Histones / Inhibitors / ITF6475 / Laboratory animals / Light levels / Nerves / neuropathy / Neurophysiology / neuroprotection / Neurotoxicity / Paclitaxel / Pain perception / Peripheral neuropathy / Prostate / Quality of life / Sensory neurons / Side effects / small fibers / Solid tumors / Transcription factors / Tumors / Vincristine