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First published on November 20, 2007; DOI: 10.1124/mol.107.041335

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Received for publication September 4, 2007.
Revised October 14, 2007.
Accepted for publication November 20, 2007.

Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking

Xiangcong Xu 1, Robert Sutak 1, Des R Richardson 1*

1 University of Sydney

* Address correspondence to: E-mail: d.richardson{at}pathology.usyd.edu.au

Abstract

Anthracyclines are effective anti-cancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron (Fe) and perturb Fe metabolism (Xu X, Persson L and Richardson DR Mol Pharmacol 68:261-271, 2005). These effects on Fe-trafficking remain poorly understood, but are important to decipher as treatment for anthracycline cardiotoxicity utilizes the chelator, dexrazoxane. Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels of the Fe-regulated genes, transferrin receptor-1 (TfR1) and N-myc downstream-regulated gene-1 (Ndrg1). This effect was mediated by Fe-depletion, as it was reversed by adding Fe and was prevented by saturating the anthracycline metal-binding site with Fe. However, DOX did not act like a typical chelator, as it did not induce cellular Fe mobilization. In the presence of DOX and 59Fe-transferrin, Fe-trafficking studies demonstrated ferritin-59Fe accumulation and decreased cytosolic-59Fe incorporation. This could induce cytosolic Fe-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 HIF-1{alpha}-independent mechanisms. Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent decreased TfR1 and Ndrg1 protein due to inhibition of translation. Hence, the effects of DOX on Fe metabolism were complex due to its multiple effector mechanisms.


Key words: Metals and chelators, Mechanisms of cell killing/apoptosis


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