Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: The role of reactive oxygen and nitrogen intermediates

The use of the potent antitumor antibiotic doxorubicin (DOX) is hampered be cause of its severe cardiac toxicity that leads to the development of cardi omyopathy and heart failure. In this study, we have developed a cell cultur e model for DOX-induced myocardial injury using primary adult rat cardiomyo cytes that were cultured in serum-free medium and exposed to 1 to 40 mu M D OX, DOX caused a dose-dependent release of sarcosolic enzyme lactate dehydr ogenase (LDH) from cultured myocytes, The release of LDH was prevented by t he cell-permeable superoxide dismutase (SOD) mimetic (MnTBAP), but was unaf fected by either cell-impermeable SOD enzyme, or manganese (II) sulfate. Eb selen, a glutathione peroxidase (GPx) mimetic, enhanced the protection of c ardiomyocytes afforded by MnTBAP, DOX caused the increased formation of oxi dants in cardiomyocytes, and MnTBAP lowered the amount of intracellular oxi dants induced by DOX, In addition, DOX selectively inactivated aconitase in cardiomyocytes, and MnTBAP partially reversed this inactivation. Ebselen f urther amplified the protective effect of MnTBAP on aconitase activity. The se 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 mi nimizing cardiotoxicity in cancer treatment is discussed. (C) 1999 Academic Press.