The role of iron in anthracycline cardiotoxicity

Abstract

The clinical use of the antitumor anthracycline Doxorubicin is limited by the risk of severe cardiotoxicity. The mechanisms underlying anthracycline-dependent cardiotoxicity are multiple and remain uncompletely understood, but many observations indicate that interactions with cellular iron metabolism are important. Convincing evidence showing that iron plays a role in Doxorubicin cardiotoxicity is provided by the protecting efficacy of iron chelation in patients and experimental models, and studies showing that iron overload exacerbates the cardiotoxic effects of the drug, but the underlying molecular mechanisms remain to be completely characterized. Since anthracyclines generate reactive oxygen species, increased iron-catalyzed formation of free radicals appears an obvious explanation for the aggravating role of iron in Doxorubicin cardiotoxicity, but antioxidants did not offer protection in clinical settings. Moreover, how the interaction between reactive oxygen species and iron damages heart cells exposed to Doxorubicin is still unclear. This review discusses the pathogenic role of the disruption of iron homeostasis in Doxorubicin-mediated cardiotoxicity in the context of current and future pharmacologic approaches to cardioprotection.

Keywords: anthracyclines; doxorubicin; heart; iron; reactive oxygen species.

FIGURE 1

Structure and simplified scheme of molecular transformations of Doxorubicin. Redox cycling between the quinone and semiquinone forms (ring C) of Doxorubicin (DOX) leads to oxygen radicals formation. The residue involved in DOXol formation following two-electron reduction of the carbonyl group in ring A is marked in blue. Oxidative pathways involving a hydroquinone-derived semiquinone lead to formation of a diquinone (rings B and C), and eventual degradation of DOX with formation of 3-methoxytphthalic acid as remnant of ring D.

FIGURE 2

Interaction of DOX with proteins of iron metabolism. The interaction of DOX with the functions of iron regulatory proteins (IRPs) and ferritin (Ft) affects iron homeostasis and may lead to ROS-dependent and independent damage and apoptotic cell death. Iron sequestration by the iron chelator dexrazoxane (DRZ) or mitochondrial ferritin FtMt may prove cardioprotective.