Prevention of doxorubicin-induced acute cardiotoxicity by an experimental antioxidant compound

Peter Deres, R. Halmosi, A. Tóth, Krisztina Kovacs, Anita Palfi, Tamas Habon, L. Czopf, T. Kalai, K. Hideg, B. Sümegi, K. Tóth

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Doxorubicin is a widely used anticancer agent, but its application is restricted by its cardiotoxic side effects. The current theory of its cardiotoxicity is based on free radical formation. The compound H-2545, having a 3-carboxamido-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole moiety, was reported to exhibit antioxidant properties and accumulate in cell membranes, scavenging free radicals at the site of formation. Therefore, we hypothesized that H-2545 could reduce the doxorubicin-induced acute deterioration of cardiac function. Langendorff-perfused rat hearts were treated with doxorabicin and/or H-2545, its metabolite H-2954, or dihydrolipoamide. High-energy phosphate levels, contractile function, lipid peroxidation, protein oxidation, and Akt phosphorylation were investigated. We also determined whether the antioxidants influenced doxorubicin toxicity on malignant cells. During perfusion with doxorubicin, the energetic and functional parameters of the myocardium were improved by adding H-2545. H-2545 significantly diminished doxorubicin-induced lipid and protein damage. On H-2545 treatment, the doxorubicin-triggered Akt phosphorylation was markedly reduced, whereas dihydrolipoamide had such an effect only at higher concentrations. H-2545 did not alter the anticancer effect of doxorubicin on malignant cell lines. We propose that the coadministration of the antioxidant H-2545 attenuates doxorubicin-induced acute cardiotoxicity without interfering with its anticancer effects. Prevention of the acute adverse effects of doxorubicin on myocardium may hinder the later development of cardiomyopathy.

Original languageEnglish
Pages (from-to)36-43
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume45
Issue number1
DOIs
Publication statusPublished - Jan 2005

Fingerprint

Doxorubicin
Antioxidants
Free Radicals
Myocardium
Phosphorylation
Cardiotoxicity
H 2545
Cardiomyopathies
Antineoplastic Agents
Lipid Peroxidation
Proteins
Perfusion
Phosphates
Cell Membrane
Lipids
Cell Line

Keywords

  • Antioxidants
  • Doxorubicin
  • Energy metabolism
  • Free radicals
  • Heart function
  • Langendorff perfusion

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Prevention of doxorubicin-induced acute cardiotoxicity by an experimental antioxidant compound. / Deres, Peter; Halmosi, R.; Tóth, A.; Kovacs, Krisztina; Palfi, Anita; Habon, Tamas; Czopf, L.; Kalai, T.; Hideg, K.; Sümegi, B.; Tóth, K.

In: Journal of Cardiovascular Pharmacology, Vol. 45, No. 1, 01.2005, p. 36-43.

Research output: Contribution to journalArticle

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