Role of acetylation in doxorubicin-induced cardiotoxicity

Abstract

As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases.

Graphical abstract

Highlights

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  Cardiotoxicity caused by DOX is an important problem to be urgently solved in cancer treatment.

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  HDACs and HATs mediated-cell death, oxidative stress and inflammation plays a pivotal role in DOX-induced cardiotoxicity.

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  Noncoding RNA mediates HDACs to provide novel insights for the development of treatments for DOX-induced cardiotoxicity.

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  SIRT activators and HDAC inhibitors are promising drug approaches to attenuate DOX-induced cardiotoxicity.