Article

Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Nature medicine (Impact Factor: 28.05). 10/2012; 18(11). DOI: 10.1038/nm.2919
Source: PubMed

ABSTRACT 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.

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Available from: Sui Zhang, May 14, 2014
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    • "The most adverse effects of DOX for clinical application are bone marrow suppression and cardiotoxicity (Zhang et al., 2012). Doxil Õ or Lipodox Õ was approved by the FDA in 1995 as the first antitumor liposome formulation in which 495% DOX was encapsulated into sterically stabilised liposomes (SSL) that were modified with polyethylene glycol (PEG). "
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    • "ion of DOX may affect the heart independently of any interactions with iron . In a recent work performed in mice whose cardiomyocytes were specifically deleted for topoisomerase - IIβ , Zhang et al . suggested that DOX - induced cardiotoxicity was mediated by topoisomerase - IIβ inhibition , which leads to transcriptome changes in cardiomyocytes ( Zhang et al . , 2012 ) . These changes are responsible for defective mitochondrial biogenesis and ROS formation . Additionally , some of the beneficial effects observed with dexrazoxane may be related to its ability to catalytically inhibit topoisomerase II , rather than its iron - chelation activity ( Vavrova et al . , 2013 ) ."
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    • "Moreover, treatment of established adriamycin cardiomyopathy is directly only to HF symptoms. There is no known therapy for reversing the underlying cardiomyopathy [17] [18]. "
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