Histone deacetylases: potential therapeutic targets in cisplatin-induced acute kidney injury

Abstract

Aim: Chemotherapy has been well shown to enhance life expectancy in patients with malignancy. However, conventional chemotherapy drugs, particularly cisplatin, are highly associated with nephrotoxicity, which limits therapeutic efficacy and impairs quality of life. Histone deacetylases (HDACs) are proteases that play significant roles in diseases by influencing protein post-translational modification and gene expression. Agents that inhibit HDAC enzymes have been developed and approved by the FDA as anticancer drugs. It is worth noting that in certain preclinical studies with tumour cell lines, the integration of HDAC modulators and cisplatin not only exerts synergistic or additive tumour-killing effects but also alleviates cisplatin nephrotoxicity. The aim of this review is to discuss the role of HDACs in cisplatin nephrotoxicity. Methods: After searching in PubMed and Web of Science databases using ‘Histone deacetylase’, ‘nephrotoxicity’, ‘cisplatin’, and ‘onconpehrology’ as keywords, studies related was compiled and examined. Results: HDAC inhibitors exert renal protective effects by inhibiting inflammation, apoptosis, oxidative stress, and promoting autophagy; whereas sirtuins play a renal protective role by regulating lipid metabolism, inhibiting inflammation and apoptosis, and protecting mitochondrial biosynthesis and mitochondrial dynamics. These potential interactions provide clues concerning targets for molecular treatment. Conclusion: This review encapsulates the function and molecular mechanisms of HDACs in cisplatin nephrotoxicity, providing the current view by which HDACs induce different biological signaling in the regulation of chemotherapy-associated renal injury. More importantly, this review exhaustively elucidates that HDACs could be targeted to develop a new therapeutic strategy in treating cisplatin nephrotoxicity, which will extend the knowledge of the biological impact and clinical implications of HDACs.