Molecular mechanism of cardiotoxicity induced by doxorubicin

The anthracycline antibiotic doxorubicin is one of the most effective antineoplastic agents against a variety of human tumors. However, clinical utility of this drug is complicated by the cumulative and irreversible development of drug-induced cardiomyopathy. Among several hypotheses to explain the doxorubicin cardiotoxicity, oxidative alteration of mitochondrial calcium regulation has been a primary mechanism by which doxorubicin elicits its myocardial toxicity.; The overall objectives of the present investigation were: (1) to determine whether mitochondria isolated from doxorubicin-treated rats exhibit dose-dependent irreversible mitochondrial dysfunction; (2) to determine whether cardiac myocytes isolated from doxorubicin-treated animals express an exaggerated response to interventions that increase cytosolic calcium; and (3) to examine the oxidative status in cardiac myocytes and assess reversibility of the drug-induced oxidative stress.; Administration of rats with doxorubicin caused a dose-dependent and cumulative decrease in cardiac mitochondrial calcium loading capacity. This suppression of calcium loading capacity was persistent and irreversible, which was further corroborated by dose-dependent and irreversible histopathological changes. The decrease in mitochondrial calcium loading capacity was abolished by cyclosporin A, indicating involvement of the induction of the mitochondrial permeability transition in the mechanism of doxorubicin cardiotoxicity. In correlation to this decreased mitochondrial calcium loading capacity, cardiac myocytes harvested from doxorubicin-treated rats exhibited an increased associated with this increased cell killing was depletion of ATP, which added further evidence supporting mitochondrial dysfunction in doxorubicin-induced cardiotoxicity. In addition, cardiac myocytes from doxorubicin-treated animals produced increased free radicals. The persistence of this increased free radical production correlated with the irreversible mitochondrial dysfunction in calcium regulation.; All these data indicate that mitochondrial dysfunction is involved in the doxorubicin cardiotoxicity; it may be that oxidative alteration in mitochondrial calcium regulation is causatively responsible for the development of doxorubicin-induced cardiomyopathy.