Iron chelation by clinically relevant anthracyclines: alteration in expression of iron-regulated genes and atypical changes in intracellular iron distribution and trafficking.
Anthracyclines are effective anticancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron and to perturb iron metabolism (Mol Pharmacol 68:261-271, 2005). These effects on iron-trafficking remain poorly understood, but they are important to decipher because treatment for anthracycline cardiotoxicity uses the chelator, dexrazoxane. Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels of the iron-regulated genes transferrin receptor-1 (TfR1) and N-myc downstream-regulated gene-1 (Ndrg1). This effect was mediated by iron depletion, because it was reversed by adding iron and it was prevented by saturating the anthracycline metal binding site with iron. However, DOX did not act like a typical chelator, because it did not induce cellular iron mobilization. In the presence of DOX and (59)Fe-transferrin, iron-trafficking studies demonstrated ferritin-(59)Fe accumulation and decreased cytosolic-(59)Fe incorporation. This could induce cytosolic iron deficiency and increase TfR1 and Ndrg1 mRNA. Up-regulation of TfR1 and Ndrg1 by DOX was independent of anthracycline-mediated radical generation and occurred via hypoxia-inducible factor-1alpha-independent mechanisms. Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent decreased TfR1 and Ndrg1 protein expression. Hence, the effects of DOX on iron metabolism were complex because of its multiple effector mechanisms.
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Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales, 2006 Australia.
Sutak
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Richardson
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D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000187:drug effects; D015251:Epirubicin / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects; D011485:Protein Binding; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D003630:Daunorubicin; D003676:Deferoxamine; D004317:Doxorubicin; D015251:Epirubicin; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D007502:Iron Chelating Agents; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D017262:Siderophores; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C480029:Tfrc protein, mouse