New iron chelators in anthracycline-induced cardiotoxicity

Abstract

The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models. The lack of interference with the antiproliferative effects of the anthracyclines also favors their use in clinical settings. The dose, however, should be carefully titrated to prevent iron depletion, which apparently also applies for other strong iron chelators. We have shown that a mere ability of a compound to chelate iron is not the sole determinant of a good cardioprotector and the protective potential does not directly correlate with the ability of the chelators to prevent hydroxyl radical formation. These findings, however, do not weaken the role of iron in doxorubicin cardiotoxicity as such, they rather appeal for further investigations into the molecular mechanisms how anthracyclines interact with iron and how iron chelation may interfere with these processes.

Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking

“…However, a major problem is their cardiotoxic effect at high cumulative doses that limit their clinical use (Gianni and Myers, 1992). The mechanism of anthracycline-mediated cardiotoxicity is unclear (Kaiserová et al, 2007), probably because of the multiple effects of these agents, including DNA binding, intercalation, alkylation, inhibition of topoisomerase II, and the generation of reactive oxygen species (ROS) (Gianni and Myers, 1992).…”

“…Anthracyclines such as doxorubicin (DOX) can directly chelate Fe(III), forming an iron complex with an overall association constant of 10 33 (May et al, 1980;Beraldo et al, 1985). Hershko and associates demonstrated that iron loading potentiates the cardiotoxic effects of anthracyclines (Hershko et al, 1993;Link et al, 1996), and some chelators can prevent this (Kaiserová et al, 2007). In fact, the clinical intervention for anthracycline cardiotoxicity involves the chelator dexrazoxane (Xu et al, 2005).…”

Mitochondrial catastrophe during doxorubicin‐induced cardiotoxicity: a review of the protective role of melatonin

“…The heart, in particular, is highly susceptible to DXR-induced oxidative damage as it is abundant in mitochondria, which are both sources and targets for ROS [86]. Furthermore, the heart has an elevated rate of oxygen consumption and limited antioxidant defense systems when compared to other tissues [87,88]. It was demonstrated in other studies that cardiomyocytes expressed low levels of catalase and that antioxidant selenium-dependent GSH-peroxidase-1 was inactivated when exposed to DXR, which subsequently decreased cytosolic antioxidant Cu-Zn superoxide dismutase [89,90].…”

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

“…The heart is particularly susceptible to Doxo-induced oxidative damage because of the large density/volume of mitochondria. These are both important sources and targets of ROS, given their high rate of oxygen consumption and lower antioxidant defenses in the heart compared with other organs, such as the liver [125,126]. Many intracellular enzymes can mediate Doxo effects.…”