Involvement of ferritin heavy chain in the preventive effect of metformin against doxorubicin-induced cardiotoxicity

Cardiology Department, University Hospital Virgen de la Arrixaca, and Department of Medicine, School of Medicine, University of Murcia, 30120 Murcia, Spain
Free Radical Biology and Medicine (Impact Factor: 5.74). 09/2012; 57. DOI: 10.1016/j.freeradbiomed.2012.09.009.


Doxorubicin is a wide-spectrum chemotherapeutic agent, although a cumulative dose may cause cardiac damage and lead to heart failure. Doxorubicin cardiotoxicity is dependent on the intracellular iron pool and manifests itself by increasing oxidative stress. Our group has recently shown the ability of metformin, an oral antidiabetic with cardiovascular benefits, to protect cardiomyocytes from doxorubicin-induced damage. This work aimed to study whether metformin is able to modulate the expression of ferritin, the major intracellular iron storage protein, in cardiomyocytes and whether it is involved in their protection. The addition of metformin to adult mouse cardiomyocytes (HL-1 cell line) induced both gene and protein expression of the ferritin heavy chain (FHC) in a time-dependent manner. The silencing of FHC expression with siRNAs inhibited the ability of metformin to protect cardiomyocytes from doxorubicin-induced damage, in terms of the percentage of cell viability, the levels of reactive oxygen species, and the activity of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase). In addition, metformin induced the activation of NF-κB in HL-1 cells, whereas preincubation with SN50, an inhibitor of NF-κB, blocked the upregulation of the FHC and the protective effect mediated by metformin. Taken together, these results provide new knowledge on the protective actions of metformin against doxorubicin-induced cardiotoxicity by identifying FHC and NF-κB as the major mediators of this beneficial effect.

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    • "Newly formed ferritin can therefore sequester iron and may paradoxically represent a defense for cardiomyocytes. These findings were recently supported by two studies demonstrating that NF-kB-mediated ferritin H chain induction plays an important role in the mitochondrial protection offered by metformin against DOX cardiotoxicity in isolated cardiomyocytes (Asensio-López et al., 2013a,b). Moreover, it has been shown that exposure of cardiomyocytes to DOX leads to higher accumulation of iron into ferritin by mechanisms that impair iron release from ferritin and/or lysosomal/proteasomal degradation of this iron-storage protein (Kwok and Richardson, 2003, 2004). "
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    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.
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