Molecular Pharmacology of the Interaction of Anthracyclines with Iron

Abstract

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.Anthracyclines are potent antineoplastic agents used extensively to treat a range of cancers, including leukemias, lymphomas, sarcomas, and carcinomas (for review, see Gewirtz, 1999). Doxorubicin, daunorubicin, and epirubicin are clinically used anthracyclines (Fig. 1). The intricate and complex cellular responses to anthracyclines hinder efforts to unveil the mechanisms involved in their cytostatic and cytotoxic actions. However, anthracyclines are proposed to disrupt macromolecular biosynthesis by various mechanisms, including DNA intercalation and the inhibition of DNA polymerase and topoisomerase II (Gewirtz, 1999). Anthracyclines can also induce DNA damage by the generation of free radicals that react with a variety of macromolecules, thus inhibiting cellular proliferation or causing apoptosis (Gewirtz, 1999). In general, the antitumor effect of anthracyclines is mainly attributed to their DNA-binding and -damaging abilities. Indeed, the pharmacological aspects of these drugs have been extensively reviewed (for reviews, see Myers, 1998;Minotti et al., 2004) and will not be discussed in depth in this article.A major problem with the clinical use of anthracyclines is their cardiotoxicity, which limits administration exceeding an accumulated dose of approximately 550 mg/m 2 (for re-

Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity

“…7d). Additionally, we found significant ( P < 0.05) differences in genes involved with iron transport and storage 32 (Supplementary Fig. 7e), chromatin remodeling and chemotherapy resistance-related gene SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) 43 (Supplementary Fig.…”

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

“…In contrast, the interaction with cisplatin and 5-fluorouracil is almost entirely p53 dependent, and could be explained by increased mutant p53 following genotoxic stress, thus providing more substrate for drug activity, resulting in stronger restoration of wild-type p53 activity. With regard to synergism with epirubicin, we speculate that APR-246 may deplete intracellular antioxidant activity,12 13 thus potentiating epirubicin-induced ROS,35 resulting in enhanced cytotoxicity. This hypothesis warrants further exploration.…”

Alteration of serum and cardiac tissue adropin, copeptin, irisin and TRPM2 expressions in DOX treated male rats

“…A side effect of chronic DOX is dose-dependent cardiotoxicity, which is characterized by dilated cardiomyopathy (DCM) and congestive heart failure (CHF) in up to 20% of cases and can develop years after treatment (Chatterjee et al 2010). Chronic cardiotoxicity may be related to generation of free radicals by iron oxidation and subsequent induction of apoptosis (Shi et al 2011), because the redox cycle of DOX in even minimally replicating cells is accompanied by release of iron ions from intracellular stores, which results in its interaction with hyrodgen peroxide and formation of hydroxyl radicals (Xu et al 2005). Plasma brain natriuretic peptide (BNP) and atrial natriuretic and chronic treatment decreases cardiac output (Solie et al 1978).…”