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Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: the role of reactive oxygen and nitrogen intermediates. Arch Biochem Biophys 1999 Aug 15;368(2):421-8

Date

08/12/1999

Pubmed ID

10441396

DOI

10.1006/abbi.1999.1337

Scopus ID

2-s2.0-0033567224 (requires institutional sign-in at Scopus site)   117 Citations

Abstract

The use of the potent antitumor antibiotic doxorubicin (DOX) is hampered because of its severe cardiac toxicity that leads to the development of cardiomyopathy and heart failure. In this study, we have developed a cell culture model for DOX-induced myocardial injury using primary adult rat cardiomyocytes that were cultured in serum-free medium and exposed to 1 to 40 microM DOX. DOX caused a dose-dependent release of sarcosolic enzyme lactate dehydrogenase (LDH) from cultured myocytes. The release of LDH was prevented by the cell-permeable superoxide dismutase (SOD) mimetic (MnTBAP), but was unaffected by either cell-impermeable SOD enzyme, or manganese (II) sulfate. Ebselen, a glutathione peroxidase (GPx) mimetic, enhanced the protection of cardiomyocytes afforded by MnTBAP. DOX caused the increased formation of oxidants in cardiomyocytes, and MnTBAP lowered the amount of intracellular oxidants induced by DOX. In addition, DOX selectively inactivated aconitase in cardiomyocytes, and MnTBAP partially reversed this inactivation. Ebselen further amplified the protective effect of MnTBAP on aconitase activity. These results suggest that the SOD mimetic MnTBAP prevents DOX-induced damage to cardiomyocytes and that the GPx mimetic ebselen synergistically enhanced the cardioprotection afforded by MnTBAP. Relevance of these findings to minimizing cardiotoxicity in cancer treatment is discussed.

Author List

Konorev EA, Kennedy MC, Kalyanaraman B

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antibiotics, Antineoplastic
Cells, Cultured
Doxorubicin
Glutathione
Glutathione Peroxidase
Heart
L-Lactate Dehydrogenase
Male
Myocardium
Nitric Oxide
Nitrogen
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
Superoxide Dismutase