Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Yeh, E.T. & Bickford, C.L. J. Am. Coll. Cardiol. 53, 2231–2247 (2009).

    Article  CAS  Google Scholar 

  2. Force, T. & Kolaja, K.L. Nat. Rev. Drug Discov. 10, 111–126 (2011).

    Article  CAS  Google Scholar 

  3. Tewey, K.M., Rowe, T.C., Yang, L., Halligan, B.D. & Liu, L.F. Science 226, 466–468 (1984).

    Article  CAS  Google Scholar 

  4. Capranico, G., Tinelli, S., Austin, C.A., Fisher, M.L. & Zunino, F. Biochim. Biophys. Acta 1132, 43–48 (1992).

    Article  CAS  Google Scholar 

  5. Lyu, Y.L. et al. Mol. Cell. Biol. 26, 7929–7941 (2006).

    Article  CAS  Google Scholar 

  6. Singal, P.K. & Iliskovic, N. N. Engl. J. Med. 339, 900–905 (1998).

    Article  CAS  Google Scholar 

  7. Myers, C. et al. Semin. Oncol. 10, 53–55 (1983).

    CAS  PubMed  Google Scholar 

  8. Martin, E. et al. Toxicology 255, 72–79 (2009).

    Article  CAS  Google Scholar 

  9. Lyu, Y.L. et al. Cancer Res. 67, 8839–8846 (2007).

    Article  CAS  Google Scholar 

  10. Lyu, Y.L. & Wang, J.C. Proc. Natl. Acad. Sci. USA 100, 7123–7128 (2003).

    Article  CAS  Google Scholar 

  11. Sohal, D.S. et al. Circ. Res. 89, 20–25 (2001).

    Article  CAS  Google Scholar 

  12. Okamura, S. et al. Mol. Cell 8, 85–94 (2001).

    Article  CAS  Google Scholar 

  13. Ogasawara, J. et al. Nature 364, 806–809 (1993).

    Article  CAS  Google Scholar 

  14. Plesca, D., Mazumder, S. & Almasan, A. Methods Enzymol. 446, 107–122 (2008).

    Article  CAS  Google Scholar 

  15. Arany, Z. et al. Proc. Natl. Acad. Sci. USA 103, 10086–10091 (2006).

    Article  CAS  Google Scholar 

  16. Lai, L. et al. Genes Dev. 22, 1948–1961 (2008).

    Article  CAS  Google Scholar 

  17. Wang, J. et al. Circ. Res. 106, 1904–1911 (2010).

    Article  CAS  Google Scholar 

  18. Wallace, K.B. Pharmacol. Toxicol. 93, 105–115 (2003).

    Article  CAS  Google Scholar 

  19. Sahin, E. et al. Nature 470, 359–365 (2011).

    Article  CAS  Google Scholar 

  20. Ju, B.G. et al. Science 312, 1798–1802 (2006).

    Article  CAS  Google Scholar 

  21. Liao, R. & Jain, M. Methods Mol. Med. 139, 251–262 (2007).

    Article  Google Scholar 

  22. Bawa-Khalfe, T., Cheng, J., Wang, Z. & Yeh, E.T. J. Biol. Chem. 282, 37341–37349 (2007).

    Article  CAS  Google Scholar 

  23. Ishii, K.A. et al. Nat. Med. 15, 259–266 (2009).

    Article  CAS  Google Scholar 

  24. Zeisberg, E.M. et al. Nat. Med. 13, 952–961 (2007).

    Article  CAS  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Edward T H Yeh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2919

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing