Korean J Pain.  2025 Apr;38(2):152-162. 10.3344/kjp.24358.

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

• Park SJ
• Lee SM
• Kang SM
• Yang HM
• Seo SK
• Lee JH

• KMID: 2566647
• DOI: http://doi.org/10.3344/kjp.24358

Abstract

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.

Keyword

Bortezomib; Cancer Pain; Chemotherapy-Induced Peripheral Neuropathy; Cisplatin; Histone Deacetylases; Paclitaxel; Peripheral Nervous System Diseases

Figure

• 

  Fig. 1 The expression of acetylated tubulin by CKD-011 in MM1.S cells. CKD-011, an HDAC6 inhibitor, was added at different concentrations, and the expression of acetylated tubulin, total tubulin, ubiquitin, acetylated histone H3, and total histone H3 was confirmed using immunoblotting. HDAC6: histone deacetylase 6.

• 

  Fig. 2 Effect of HDAC6 inhibitor, CKD-011, in a bortezomib-induced peripheral neuropathy rat model. Effect of CKD-011, an HDAC6 inhibitor, in a rat model of bortezomib-induced peripheral neuropathy. CKD-011 was administered at 10, 20, or 40 mg/kg once daily for 10 days (A–E) or 15 days (F–H). Mechanical hypersensitivity or body weight was measured 3 hr (A, B) or 24 hr (C–H) after the last dose. Each bar represents mechanical withdrawal threshold in time or grams, or body weight in grams. Results are shown as mean ± standard error of the mean. HDAC6: histone deacetylase 6. ##P = 0.001; ###P < 0.001 compared to vehicle; *P = 0.02 (bortezomib + CKD-011 10 mg/kg), *P = 0.01 (bortezomib + CKD-011 20 mg/kg); ***P < 0.001 compared to bortezomib.

• 

  Fig. 3 Effect of HDAC6 inhibitor, CKD-011, in an oxaliplatin-induced peripheral neuropathy rat model. CKD-011 (5 or 10 mg/kg) or gabapentin (60 mg/kg) was administered intraperitoneally once a day for 10 times (5 times a week) (A–E) or 15 times (F–H). Mechanical hypersensitivity or body weight was measured was measured 3 hr (A, B) or 24 hr (C–H) after the last dose. Results are shown as mean ± standard error of the mean. HDAC6: histone deacetylase 6. ###P < 0.001 compared to vehicle; *P = 0.05; **P = 0.008; ***P < 0.001 compared to oxaliplatin.

• 

  Fig. 4 Effect of HDAC6 inhibitor, CKD-011, on cisplatin-induced chemotherapy-induced peripheral neuropathy. CKD-011 (5 or 10 mg/kg) or gabapentin (60 mg/kg) was administered intraperitoneally once a day for 5 times (5 times a week) (A–E) or 10 times (F–H). Mechanical hypersensitivity or body weight was measured was measured 3 hr (A, B) or 24 hr (C–H) after the last dose. Results are shown as mean ± standard error of the mean. HDAC6: histone deacetylase 6. ###P < 0.001 compared to vehicle; *P = 0.02 (E); *P = 0.03 (H); **P = 0.003; ***P < 0.001 compared to cisplatin.

• 

  Fig. 5 Effect of the HDAC6 inhibitor CKD-011 in the paclitaxel-induced peripheral neuropathy rat model. Gabapentin (60 mg/kg) or 5 mg/kg, 10 mg/kg of CKD-011 was administered intraperitoneally to the paclitaxel-induced chemotherapy-induced peripheral neuropathy rat model. CKD-011 or gabapentin was administered intraperitoneally once a day for 10 times (5 times a week) (A–E) or 15 times (F–H). Mechanical hypersensitivity or body weight was measured was measured 3 hr (A, B) or 24 hr (C–H) after the last dose. Results are shown as mean ± standard error of the mean. HDAC6: histone deacetylase 6. ###P < 0.001 compared to vehicle; ***P < 0.001 compared to paclitaxel.

• 

  Fig. 6 Sciatic nerve electron microscopy examination. Electron microscopy was used to analyze the effects of the HDAC6 inhibitor CKD-011 on bortezomib-induced peripheral neuropathy in rat sciatic nerve tissue (A). Sciatic nerve tissue from rats with cisplatin- or oxaliplatin-induced peripheral neuropathy was examined by electron microscopy to evaluate the effect of the HDAC6 inhibitor CKD-011 (B, C). Transmission electron microscopy analysis of paclitaxel-induced peripheral neuropathy in rats treated with the HDAC6 inhibitor CKD-011 (D). Graphical consequences of axonal and myelin damage (E–L). A–D shows 2,000× magnification (voltage condition 60 kV). Results are shown as mean ± standard error of the mean. HDAC6: histone deacetylase 6. #P = 0.03 compared to vehicle; **P = 0.001; ***P < 0.001 compared to bortezomib. ###P < 0.001 compared to vehicle; *P = 0.01; **P = 0.007; ***P < 0.001 compared to oxaliplatin. ###P < 0.001 compared to vehicle; **P = 0.001 (I, cisplatin + CKD-011 5 mg/kg, cisplatin + CKD-011 10 mg/kg), **P = 0.007 (I, cisplatin + gabapentin 60 mg/kg), **P = 0.002 (J, cisplatin + gabapentin 60 mg/kg); ***P < 0.001 compared to cisplatin. **P = 0.002 compared to paclitaxel.

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