Identification of the molecular basis of doxorubicin-induced cardiotoxicity

• Published in: Nature medicine Vol. 18; no. 11; pp. 1639 - 1642
• Main Authors: Zhang, Sui, Liu, Xiaobing, Bawa-Khalfe, Tasneem, Lu, Long-Sheng, Lyu, Yi Lisa, Liu, Leroy F, Yeh, Edward T H
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2012; Nature Publishing Group
• Subjects: 631/92/609; 692/699/75; 692/700/565/2194; Animals; Apoptosis - drug effects; Biomedicine; brief-communication; Cancer Research; Cardiology; Cardiotoxins; Complications and side effects; Deoxyribonucleic acid; DNA; DNA Topoisomerases, Type II - genetics; DNA-Binding Proteins - genetics; Doxorubicin; Doxorubicin - toxicity; Heart Failure - chemically induced; Humans; Infectious Diseases; Metabolic Diseases; Mice; Mitochondrial Turnover - drug effects; Molecular biology; Molecular Medicine; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neurosciences; Physiological aspects; Poly-ADP-Ribose Binding Proteins; Reactive Oxygen Species - metabolism; Sequence Deletion; Toxicity
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2919

Doxorubicin, which induces tumor cell death through effects on topoisomerase-II, is a commonly used chemotherapeutic agent but has the substantial drawback of causing cardiotoxicity. Edward T.H.Yeh and his colleagues now show that doxorubicin-induced cardiotoxicity in mice is due to the deleterious effects of doxorubicin on topoisomerase-IIβ in cardiomyocytes, leading to alterations in gene expression, mitochondrial dysfunction and cell death. Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.