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Abstract
This study investigated the effect of anthracycline antibiotics, mitomycin C, and menadione on oxygen consumption and hydrogen peroxide production by intact, beating, rat heart myocytes. Doxorubicin produced a dose-dependent increase in the rate of cyanide-resistant respiration by beating myocytes. The anthracycline analogs 4-demethoxydaunorubicin, 4′-epidoxorubicin, 4′-deoxydoxorubicin, and menogaril, as well as the anticancer quinones mitomycin C and menadione, also significantly increased oxygen consumption by cardiac myocytes. However, 5-iminodaunorubicin (which has a substituted quinone group) and mitoxantrone (which is not easily reduced by flavin dehydrogenases) had no effect on cardiac respiration. Both catalase (43%) and acetylated cytochrome c (19%) significantly decreased oxygen consumption that had been stimulated by doxorubicin; furthermore, extracellular hydrogen peroxide production was increased from undetectable control levels to 1.30 ± 0.02 nmol/min/107 myocytes (n = 4, P < 0.01) in the presence of 400 μM doxorubicin. These experiments suggest that the anthracycline antibiotics and other anticancer quinones stimulate cardiac oxygen radical production in intact heart myocytes; such a free radical cascade could contribute to the cardiac toxicity of these drugs.
Highlights
The anticancer quinones, including the anthracycline antibiotics and mitomycin C, are widely used for the treatment of hematopoietic malignancies and cancers of the breast and bladder [1]
Several lines of evidence support the possibility that stimulation of superoxide anion, hydrogen peroxide, and a chemical species with the characteristics of the hydroxyl radical in the heart after reduction of the quinone moiety by complex I of the mitochondrial electron transport chain [9], NADPH:cytochrome P-450 reductase associated with the sarcoplasmic reticular membrane, or cytoplasmic xanthine dehydrogenase [10] plays an important role in the mechanism of anthracycline cardiac toxicity [11, 12]
If reactive oxygen species are produced at these intracellular sites in intact heart cells [13], oxidative stress itself might explain the characteristic picture of mitochondrial swelling, sarcotubular vacuolization, and myofibrillar loss produced by anthracycline quinones [1]
Summary
The anticancer quinones, including the anthracycline antibiotics and mitomycin C, are widely used for the treatment of hematopoietic malignancies and cancers of the breast and bladder [1]. Many different hypotheses have been suggested to explain the myocardial injury produced by antineoplastic quinones [5, 6] These hypotheses include the observation that the formation of a doxorubicin-iron complex may enhance the formation of strong oxidants toxic to the heart [7]; cardiac toxicity could occur through drug-induced effects on iron-binding proteins [8]. Several lines of evidence support the possibility that stimulation of superoxide anion, hydrogen peroxide, and a chemical species with the characteristics of the hydroxyl radical in the heart after reduction of the quinone moiety by complex I of the mitochondrial electron transport chain [9], NADPH:cytochrome P-450 reductase associated with the sarcoplasmic reticular membrane, or cytoplasmic xanthine dehydrogenase [10] plays an important role in the mechanism of anthracycline cardiac toxicity [11, 12]. Drug-induced oxygen radical formation appears to be at least one mechanism involved in the toxicity of anthracyclines for neonatal heart cells
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