Abstract
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 Pharmacol68:261-271, 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 59Fe-transferrin, iron-trafficking studies demonstrated ferritin-59Fe accumulation and decreased cytosolic-59Fe 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-1α-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.
Footnotes
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This project was supported by a fellowship and grants from the National Health and Medical Research Council of Australia.
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D.R.R. designed the study, obtained grant funding, and wrote the manuscript. X.X. and R.S. designed studies, wrote the manuscript, and performed experiments.
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ABBREVIATIONS: ROS, reactive oxygen species; DOX, doxorubicin; Tf, transferrin; TfR1, transferrin receptor-1; ferritin-H, ferritin heavy chain; ferritin-L, ferritin light chain; IRP, iron regulatory protein; DAU, daunorubicin; EPI, epirubicin; Ndrg1, N-myc downstream-regulated gene-1; DFO, desferrioxamine; PIH, pyridoxal isonicotinoyl hydrazone; MEF, murine embryo fibroblast; HIF-1α, hypoxia inducible factor-1α; apo-Tf, apotransferrin; PAGE, polyacrylamide gel electrophoresis; FPLC, fast pressure liquid chromatography; RT, reverse transcriptase; PCR, polymerase chain reaction; FAC, ferric ammonium citrate; CON, control medium; F, fraction; VEGF, vascular endothelial growth factor; SOD, superoxide dismutase; RS, radical scavenger(s); 5-i-DAU, 5-imino-daunorubicin.
- Received September 1, 2007.
- Accepted November 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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