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Identification of the molecular basis of doxorubicin-induced cardiotoxicity

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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Figure 1: Time-dependent changes in the transcriptome after acute doxorubicin treatment.
Figure 2: Changes in mitochondrial function and structure after acute doxorubicin treatment, and in heart function after chronic doxorubicin treatment.

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Acknowledgements

We thank C.H. Ren for expert technical assistance and F.M. Lin and H. Dou for conducting studies on mitochondria DNA. W.C. Claycomb (Louisiana State University Health Science Center) provided HL-1 cells. This study is supported by the Cancer Prevention Research Institute of Texas and McNair Medical Institute (E.T.H.Y.), US National Institutes of Health grant CA102463 (to L.F.L.), the New Jersey Commission on Cancer Research Grant 06-2419-CCR-EO, US Department of Defense Idea Award W81XWH-07-1-0407 and Concept Award W81XWH06-1-0514 (to Y.L.L.).

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E.T.H.Y. and L.F.L. conceived the project. S.Z., X.L., T.B.-K., L.-S.L. and Y.L.L. performed experiments and data analysis. E.T.H.Y. and S.Z. wrote the manuscript with editorial input from L.F.L. and Y.L.L.

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Correspondence to Edward T H Yeh.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Tables 1 and 2 (PDF 896 kb)

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Zhang, S., Liu, X., Bawa-Khalfe, T. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18, 1639–1642 (2012). https://doi.org/10.1038/nm.2919

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