Potential of histone deacetylase 6 inhibitors in alleviating chemotherapy-induced peripheral neuropathy.

Background: Histone deacetylase 6 (HDAC6), belonging to class IIb of histone deacetylases, regulates the acetylation of the cytoplasmic protein α-tubulin. The overexpression of HDAC6 is linked to the development of tumors, and inhibiting HDAC6 is known to trigger apoptosis in multiple myeloma cells. In addition to its application in cancer treatment, bortezomib, a proteasome inhibitor, is widely used in managing multiple myeloma and has shown effectiveness in patients with both newly diagnosed and relapsed disease. However, the treatment regimen may be delayed or discontinued due to the risk of peripheral neuropathy, a significant non-hematologic side effect. Methods: Animal models of peripheral neuropathy induced by various anti-cancer drugs were established, confirming the potential of HDAC6 inhibitors as a treatment for this condition. Six- to eight-week-old male Sprague Dawley rats were utilized to create these models. Mechanical allodynia and electron microscopy served as indicators of peripheral neuropathy. The HDAC6 inhibitor CKD-011 was administered at doses of 5, 10, 20, and 40 mg/kg. Results: In an animal model of bortezomib-induced peripheral neuropathy, CKD-011, an HDAC6 inhibitor, effectively ameliorated peripheral neuropathy. Similarly, CKD-011 administration demonstrated recovery from peripheral neuropathy in models induced with oxaliplatin, paclitaxel, and cisplatin. Conclusions: These findings suggest that HDAC6 inhibitors have the potential to mitigate peripheral neuropathy induced by chemotherapeutic agents.