Neuroprotective in vitro effects of histone deacetylase 6-selective inhibitor SW-100 toward oxaliplatin-derived toxicity

Chemotherapy-induced peripheral neuropathy is a common side effect of chemotherapy drugs. Currently, no effective preventive strategies or treatments are available. In recent years, histone deacetylase inhibitors (HDACis), initially approved for hematologic malignancies, have been proposed for neuroprotective purposes. HDACis inhibit histone deacetylases, a group of enzymes involved in the regulation of both histone and nonhistone proteins. In this study, we tested the antitumorigenic abilities of 3 different HDACis (SAHA, romidepsin, and SW-100) in combination with oxaliplatin (OHP) in 3 colorectal cancer cell lines (HT-29, HCT-15, and Caco-2). OHP is the gold standard antineoplastic therapy for the treatment of colorectal cancer, and it is also known to induce peripheral neuropathy, which affects patients' quality of life. OHP treatment often forces a reduction of the clinical effective drug dose, or even an interruption in anticancer treatment. Therefore, we also assessed the efficacy of 3 HDACis in mitigating the neurotoxicity induced by OHP in E15 rat embryo dorsal root ganglia. Apoptotic and cell proliferation pathways were tested through immunoblot analysis, immunofluorescence, and cell survival analysis. The results of this study show that SW-100, a selective histone deacetylase 6 inhibitor, induces apoptosis and reduces cell viability in both HT-29 and HCT-15 when used in combination with OHP. Besides its antineoplastic activity, SW-100 can protect against OHP neurotoxicity, limiting the activation of caspase 3 and selectively inducing α-tubulin acetylation to possibly stabilize axonal transport. In conclusion, we propose SW-100 and OHP as a viable combination for future studies on the treatment of chemotherapy-induced peripheral neuropathy. Significance Statement: Chemotherapy-induced peripheral neuropathy is a common side effect of oxaliplatin, a drug used for the treatment of colorectal cancer. This study demonstrated that in vitro cotreatment with the histone deacetylase 6 selective inhibitor, SW-100, attenuates the neurotoxic effect of oxaliplatin while maintaining the efficacy of the treatment.