Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats

Karol L. Thompson, Barry A. Rosenzweig, Jun Zhang, Alan D. Knapton, Ronald Honchel, Steven E. Lipshultz, Jacques Retief, Frank D. Sistare, Eugene H. Herman

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Purpose: The antineoplastic anthracycline doxorubicin can induce a dose-dependent cardiomyopathy that limits the total cumulative dose prescribed to cancer patients. In both preclinical and clinical studies, pretreatment with dexrazoxane, an intracellular iron chelator, partially protects against anthracycline-induced cardiomyopathy. To identify potential additional cardioprotective treatment strategies, we investigated early doxorubicin-induced changes in cardiac gene expression. Methods: Spontaneously hypertensive male rats (n = 47) received weekly intravenous injections of doxorubicin (3 mg/kg) or saline 30 min after pretreatment with dexrazoxane (50 mg/kg) or saline by intraperitoneal injection. Cardiac samples were analyzed 24 h after the first (n = 20), second (n=13), or third (n =14) intravenous injection on days 1, 8, or 15 of the study, respectively. Results: Rats receiving three doses of doxorubicin had minimal myocardial alterations that were attenuated by dexrazoxane. Cardiac expression levels of genes associated with the Nrf2-mediated stress response were increased after a single dose of doxorubicin, but not affected by cardioprotectant pretreatment. In contrast, an early repressive effect of doxorubicin on transcript levels of genes associated with mitochondrial function was attenuated by dexrazoxane pretreatment. Dexrazoxane had little effect on gene expression by itself. Conclusions: Genomic analysis provided further evidence that mitochondria are the primary target of doxorubicininduced oxidative damage that leads to cardiomyopathy and the primary site of cardioprotective action by dexrazoxane. Additional strategies that prevent the formation of oxygen radicals by doxorubicin in mitochondria may provide increased cardioprotection.

Original languageEnglish (US)
Pages (from-to)303-314
Number of pages12
JournalCancer Chemotherapy And Pharmacology
Volume66
Issue number2
DOIs
StatePublished - Jul 1 2010

Keywords

  • Anthracycline
  • Cardioprotection
  • Cardiotoxicity
  • Dexrazoxane
  • Doxorubicin
  • Microarray

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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    Thompson, K. L., Rosenzweig, B. A., Zhang, J., Knapton, A. D., Honchel, R., Lipshultz, S. E., Retief, J., Sistare, F. D., & Herman, E. H. (2010). Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats. Cancer Chemotherapy And Pharmacology, 66(2), 303-314. https://doi.org/10.1007/s00280-009-1164-9