Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity

Paulo J. Oliveira, James A. Bjork, Maria S. Santos, Richard L. Leino, M. Kent Froberg, António J. Moreno, Kendall B Wallace

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183 Scopus citations

Abstract

The cardiotoxicity associated with doxorubicin (DOX) therapy limits the total cumulative dose and therapeutic success of active anticancer chemotherapy. Cardiac mitochondria are implicated as primary targets for DOX toxicity, which is believed to be mediated by the generation of highly reactive free radical species of oxygen from complex I of the mitochondrial electron transport chain. The objective of this study was to determine if the protection demonstrated by carvedilol (CV), a β-adrenergic receptor antagonist with strong antioxidant properties, against DOX-induced mitochondrial-mediated cardiomyopathy [Toxicol. Appl. Pharmacol. 185 (2002) 218] is attributable to its antioxidant properties or its β-adrenergic receptor antagonism. Our results confirm that DOX induces oxidative stress, mitochondrial dysfunction, and histopathological lesions in the cardiac tissue, all of which are inhibited by carvedilol. In contrast, atenolol (AT), a β-adrenergic receptor antagonist lacking antioxidant properties, preserved phosphate energy charge but failed to protect against any of the indexes of DOX-induced oxidative mitochondrial toxicity. We therefore conclude that the cardioprotective effects of carvedilol against DOX-induced mitochondrial cardiotoxicity are due to its inherent antioxidant activity and not to its β-adrenergic receptor antagonism.

Original languageEnglish (US)
Pages (from-to)159-168
Number of pages10
JournalToxicology and Applied Pharmacology
Volume200
Issue number2
DOIs
StatePublished - Oct 15 2004

Bibliographical note

Funding Information:
This work was supported by the NIH grant HL 58016. Paulo J. Oliveira is supported by a grant from the Portuguese Foundation for Science and Technology (PRAXIS XXI/BD/21494/99). The expert assistance of Jamie Denninger, Jessica Berthiaume, and Tim O'Brien is greatly acknowledged.

Keywords

  • Atenolol
  • Carvedilol
  • DMSO
  • DOX
  • Doxorubicin
  • Heart
  • Mitochondria
  • Mitochondrionopathy
  • Oxidative damage
  • Permeability transition pore
  • TPP
  • doxorubicin
  • mitochondrial transmembrane potential
  • tetraphenylphosphonium cation
  • ΔΨ

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