Histone Deacetylase Inhibitors Promote the Anticancer Activity of Cisplatin: Mechanisms and Potential.

Cisplatin is a widely used DNA-targeting anticancer drug. Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation, changing chromatin structure and accessibility of genomic DNA by the genotoxic drug. As a consequence, HDACi could promote cisplatin cytotoxicity. Hence, the underlying mechanisms by which HDACi alter the action pathways of cisplatin to promote its anticancer activity have attracted increasing attention during the past decades. It has been commonly accepted that HDACi elevate the acetylation level of histones to release genomic DNA to cisplatin attack, increasing the level of cisplatin-induced DNA lesions to promote cisplatin cytotoxicity. However, how the HDACi-enhanced cisplatin lesion on DNA impacts the downstream biological processes, and whether the promotion of HDACi to cisplatin activity is attributed to their inherent anticancer activity or to their induced elevation of histone acetylation, have been in debate. Several studies showed that HDACi-enhanced DNA lesion could promote cisplatin-induced apoptosis, cell cycle arrest, and reactive oxygen species (ROS) generation, subsequently promoting cisplatin efficiency. In contrast, HDACi-induced elimination of ROS and inhibition of ferroptosis were thought to be the main ways by which HDACi protect kidneys from acute injury caused by cisplatin. Based on our recent research, we herein review and discuss the advances in research on the mechanisms of HDACi-induced enhancement in cisplatin cytotoxicity. Given that histone acetyltransferase (HAT) inhibitors also show an effect enhancing cisplatin cytotoxicity, we will discuss the diverse roles of histone acetylation in cancer therapy in addition to the synergistic anticancer effect and potential of HDACi with genotoxic drugs and radiotherapy.