Comparison of Different Iron Chelators as Protective Agents Against Acute Doxorubicin-induced Cardiotoxicity

doi:10.1006/jmcc.1994.1136

Journal of Molecular and Cellular Cardiology

Volume 26, Issue 9, September 1994, Pages 1179-1185

https://doi.org/10.1006/jmcc.1994.1136 Get rights and content

Abstract

Doxorubicin (Dox) is a widely used antineoplastic agent. Irreversible cardiomyopathy is a serious and dose-limiting side effect after chronic administration. The iron chelating bispiperazinedione ICRF-187 is currently the only drug which affords protection against Dox-induced cardiotoxicity. To compare the protective value of structurally unrelated iron chelators, isolated mice atria were exposed to Dox (30 μM) and either the hydroxamate desferrioxamine (DFO, 200 and 500 μM), EDTA (200 μM) or the hydroxypyridones CP44 (200 μM), CP51 (200 μM), and CP93 (200 μM) and ICRF-187 (200 and 500 μM). The nitroxide TEMPO (5 mM) lacks iron chelating properties but was used to prevent redox cycling or iron and scavenge superoxide. All iron chelators, except EDTA, CP93 and CP44, were modestly protective against a Dox-induced decrease in contractile force. As a single agent the hydroxypyridones decreased atrial contractile force. At a concentration of 200 μM, DFO was the most effective protector of the chelators tested. However, this effect disappeared when a concentration of 500 μM was used. This in contrast to ICRF-187 for which a concentration-dependent inhibition of Dox-induced decrease in contractile force was observed. TEMPO exerted a biphasic response consisting of a two-fold increase in contractile force, followed by a decrease in force and irregular contractions. In this model TEMPO lacked any perspective as a cardioprotectant. We conclude that at 200 μM, DFO was the most effective agent to afford protection against Dox-mediated atrial malfunction. However, at 500 μM, DFO was not effective whereas ICRF-187 afforded partial protection. Hydroxipyridones were found to be of limited value because of a negative inotropic effect on the isolated atria.

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Anthracyclines have been an integral part of chemotherapeutic regimen since their discovery in 1960s. Its beneficial effects span from hematological malignancies to solid tumors. Recently, anthracyclines have come under scrutiny due to their cardiotoxic effects. Although medications, such as dexrazoxane proved to curb some of the deleterious cardiac effects, they are unable to fully ameliorate toxicity. A key to combat the unwanted effects of anthracyclines is to understand the underlying mechanism(s). Therefore, this chapter identifies risk factors associated with cardiotoxicity, illuminates the key molecular mechanisms, and suggests some of the therapeutic strategies to attenuate, if not to ameliorate, anthracycline-mediated cardiotoxicity.
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The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.
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Original ArticleComparison of Different Iron Chelators as Protective Agents Against Acute Doxorubicin-induced Cardiotoxicity

Abstract

Original Article
Comparison of Different Iron Chelators as Protective Agents Against Acute Doxorubicin-induced Cardiotoxicity