Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Nat Med. 2012 Nov;18(11):1639-42. doi: 10.1038/nm.2919. Epub 2012 Oct 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cardiotoxins*
  • DNA Topoisomerases, Type II / genetics
  • DNA-Binding Proteins / genetics
  • Doxorubicin / toxicity*
  • Heart Failure / chemically induced
  • Humans
  • Mice
  • Mitochondrial Turnover / drug effects*
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / metabolism
  • Myocytes, Cardiac* / pathology
  • Poly-ADP-Ribose Binding Proteins
  • Reactive Oxygen Species / metabolism
  • Sequence Deletion


  • Cardiotoxins
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Reactive Oxygen Species
  • Doxorubicin
  • DNA Topoisomerases, Type II
  • TOP2B protein, human
  • Top2b protein, mouse

Associated data

  • GEO/GSE40289