Dietary vitamin E decreases doxorubicin-induced oxidative stress without preventing mitochondrial dysfunction.
ABSTRACT Doxorubicin (DOX) is a widely prescribed antineoplastic and although the precise mechanism(s) have yet to be identified, DOX-induced oxidative stress to mitochondrial membranes is implicated in the pathogenic process. Previous attempts to protect against DOX-induced cardiotoxicity with alpha-tocopherol (vitamin E) have met with limited success, possibly as a result of inadequate delivery to relevant subcellular targets such as mitochondrial membranes. The present investigation was designed to assess whether enrichment of cardiac membranes with alpha-ocopherol is sufficient to protect against DOX-induced mitochondrial cardiotoxicity. Adult male Sprague-Dawley rats received seven weekly subcutaneous injections of 2 mg/kg DOX and fed either standard diet or diet supplemented with alpha-tocopherol succinate. Treatment with a cumulative dose of 14 mg/kg DOX caused mitochondrial cardiomyopathy as evidenced by histology, accumulation of oxidized cardiac proteins, and a significant decrease in mitochondrial calcium loading capacity. Maintaining rats on the alpha-tocopherol supplemented diet resulted in a significant (two- to four-fold) enrichment of cardiac mitochondrial membranes with alpha-tocopherol and diminished the content of oxidized cardiac proteins associated with DOX treatment. However, dietary alpha-tocopherol succinate failed to protect against mitochondrial dysfunction and cardiac histopathology. From this we conclude that although dietary vitamin E supplementation enriches cardiac mitochondrial membranes with alpha-tocopherol, either (1) this tocopherol enrichment is not sufficient to protect cardiac mitochondrial membranes from DOX toxicity or (2) oxidative stress alone is not responsible for the persistent mitochondrial cardiomyopathy caused by long-term DOX therapy.
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ABSTRACT: Adriamycin is a widely used anticancer agent but the cumulative dose-dependent cardiotoxicity severely limits the use of Adriamycin in the treatment of neoplastic diseases. Recent evidence suggests that Adriamycin forms reactive free radical species which may oxidize cellular components and produce the cardiomyopathy. Sulfhydryl donors and antioxidants have been effective in preventing acute Adriamycin cardiotoxicity in animal models presumably by scavenging the free radicals generated by Adriamycin. The sulfhydryl donors, namely cysteamine and N-acetyl cysteine, do not interfere with Adriamycin's antitumor activity. The results from these studies give considerable hope that the chronic cardiotoxicity from Adriamycin may be attenuated in people, thereby givinh additional therapeutic benefit from this antitumor agent.Life Sciences 11/1981; 29(14):1393-401. · 2.56 Impact Factor
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ABSTRACT: Doxorubicin (Adriamycin) is an anthracycline antibiotic with broad antineoplastic activity. However, the clinical success is limited by the incidence of cumulative cardiomyopathy. In vitro, doxorubicin elicits a cyclosporine A-sensitive release of calcium from cardiac mitochondria. It has been suggested that this leads to mitochondrial calcium cycling and depolarization of membrane potential, which may account for the inhibition of mitochondrial respiration and cytotoxicity observed with the drug. Implication of a similar mechanism in the manifestation of clinical doxorubicin toxicity requires evidence for a disruption of mitochondrial calcium homeostasis following chronic in vivo administration. Cardiac mitochondria isolated from doxorubicin-treated rats (2 mg/kg/week, s.c. x 13 weeks) had a lower RCR but no change in ADP/O compared to controls and exhibited an enhanced cyclosporine A-sensitive release of mitochondrial calcium. Associated with this was a calcium-induced depolarization of membrane potential, which was inhibited by either cyclosporine A or ruthenium red suggesting the induction of mitochondrial calcium cycling following chronic doxorubicin treatment. The persistence of these effects on mitochondrial calcium regulation 4-7 days after the last drug treatment is consistent with the cumulative cardiotoxicity associated with doxorubicin therapy. Cardiac mitochondria isolated from rats treated with iminodaunorubicin, a noncardiotoxic analog of doxorubicin, showed no differences from control suggesting that this disruption of mitochondrial calcium homeostasis in vivo may be an important determinant of the cardiomyopathy observed clinically with doxorubicin.Toxicology and Applied Pharmacology 01/1995; 129(2):214-22. · 3.98 Impact Factor
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ABSTRACT: We previously reported the induction of calcium-dependent calcium release and depolarization of membrane potential of cardiac mitochondria from rats treated chronically (13 weeks) with doxorubicin. The fact that this was inhibited by cyclosporine A and ruthenium red suggests induction of the mitochondrial permeability transition and calcium cycling. The objective of this investigation was to characterize the cumulative dose-dependent interference with mitochondrial calcium transport by doxorubicin and to assess whether alteration of mitochondrial calcium regulation is manifested as an increased sensitivity to calcium-induced injury to cardiomyocytes isolated from rats exposed in vivo. Mitochondria or cardiomyocytes were isolated from rats treated with 2 mg/kg/week doxorubicin s.c. for 1-9 weeks. Mitochondria isolated from hearts of doxorubicin-treated rats exhibited a dose-dependent increase in sensitivity to calcium-induced calcium release and membrane depolarization, both of which were inhibited by cyclosporine A. Cardiomyocytes isolated from rats treated for 6 weeks with doxorubicin expressed an increased sensitivity to calcium-induced cell killing. The calcium intolerance was prevented by adding either cyclosporine A or ruthenium red to block mitochondrial calcium cycling. These data demonstrate that doxorubicin treatment in vivo causes: (1) a dose-dependent interference with mitochondrial calcium transport and calcium-dependent regulation of membrane potential indicative of induction of the mitochondrial permeability transition, and (2) an increased sensitivity to calcium-induced loss of cell viability. The fact that blocking mitochondrial calcium cycling protected cardiomyocytes from the calcium intolerance suggests that altered regulation of mitochondrial calcium transport may be a critical event in doxorubicin-induced cardiomyopathy.Journal of Molecular and Cellular Cardiology 06/1996; 28(5):1023-32. · 5.15 Impact Factor