Molecular pharmacology of the interaction of anthracyclines with iron
2005 (English)In: Molecular Pharmacology, ISSN 0026-895X, Vol. 68, no 2, 261-271 p.Article in journal (Refereed) Published
Although anthracyclines such as doxorubicin are widely used antitumor agents, a major limitation for their use is the development of cardiomyopathy at high cumulative doses. This severe adverse side effect may be due to interactions with cellular iron metabolism, because iron loading promotes anthracyclineinduced cell damage. On the other hand, anthracycline-induced cardiotoxicity is significantly alleviated by iron chelators (e.g., desferrioxamine and dexrazoxane). The molecular mechanisms by which anthracyclines interfere with cellular iron trafficking are complex and still unclear. Doxorubicin can directly bind iron and can perturb iron metabolism by interacting with multiple molecular targets, including the iron regulatory proteins (IRP) 1 and 2. The RNA-binding activity of these molecules regulates synthesis of the transferrin receptor 1 and ferritin, which are crucial proteins involved in iron uptake and storage, respectively. At present, it is not clear whether doxorubicin affects IRP1-RNA-binding activity by intracellular formation of doxorubicinol and/or by generation of the doxorubicin-iron(III) complex. Furthermore, doxorubicin prevents the mobilization of iron from ferritin by a mechanism that may involve lysosomal degradation of this protein. Prevention of iron mobilization from ferritin would probably disturb vital cellular functions as a result of inhibition of essential iron-dependent proteins, such as ribonucleotide reductase. This review discusses the molecular interactions of anthracyclines with iron metabolism and the development of cardioprotective strategies such as iron chelators. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.
Place, publisher, year, edition, pages
2005. Vol. 68, no 2, 261-271 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-31884DOI: 10.1124/mol.105.013383Local ID: 17715OAI: oai:DiVA.org:liu-31884DiVA: diva2:252707