Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction.
The role of iron in anthracycline toxicity was studied in rats in vivo in intact animals and in vitro in heart cell cultures. In animals treated with 8 mg/kg doxorubicin, iron loading resulted in severe weight loss and a twofold increase in rate of mortality. Studies in cultured heart cells aimed at defining the subcellular target of interaction between iron and anthracycline toxicity showed no evidence of anthracycline-induced damage to sarcolemmal thiolic enzymes represented by 5'-nucleotidase and only a limited increase in lysosomal fragility as monitored by an increase in beta-hexosaminidase activity in cell homogenates and its release into the culture medium. By contrast, doxorubicin treatment resulted in a marked inhibition of mitochondrial function as monitored by a decrease in carbon 14-labeled palmitate utilization, to 33% +/- 4% of controls, and prior iron loading resulted in a further decrease in palmitate utilization, to 18% +/- 3% of controls. Conversely, iron-chelation treatment by either deferoxamine or deferiprone (L1) eliminated the harmful effects of iron loading and resulted in a partial inhibition of doxorubicin toxicity in both normal and iron-loaded cells. Our studies represent the first demonstration in intact animals of the potentiation of anthracycline toxicity by iron overload. They also indicate that mitochondria represent an important target of combined iron-anthracycline toxicity. These observations provide new insights into the mechanism of anthracycline cardiotoxicity and may be useful in developing better strategies for tumor therapy.
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Department of Human Nutrition and Metabolism, Hebrew University, Hadassah Medical School, Israel.
Tirosh
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Pinson
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Hershko
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C
D000818:Animals; D018943:Anthracyclines / Q000506:poisoning*; D000903:Antibiotics, Antineoplastic / Q000506:poisoning; D002478:Cells, Cultured; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology; D004317:Doxorubicin / Q000506:poisoning*; D005260:Female; D006321:Heart / Q000187:drug effects*; D007501:Iron / Q000502:physiology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D004317:Doxorubicin; D007501:Iron; D007770:L-Lactate Dehydrogenase; D001619:beta-N-Acetylhexosaminidases; D003676:Deferoxamine