Flavonoids as protectors against doxorubicin cardiotoxicity: Role of iron chelation, antioxidant activity and inhibition of carbonyl reductase

Abstract

Anthracycline antibiotics (e.g. doxorubicin and daunorubicin) are among the most effective and widely used anticancer drugs. Unfortunately, their clinical use is limited by the dose-dependent cardiotoxicity. Flavonoids represent a potentially attractive class of compounds to mitigate the anthracycline cardiotoxicity due to their iron-chelating, antioxidant and carbonyl reductase-inhibitory effects. The relative contribution of various characteristics of the flavonoids to their cardioprotective activity is, however, not known. A series of ten flavonoids including quercetin, quercitrin, 7-monohydroxyethylrutoside (monoHER) and seven original synthetic compounds were employed to examine the relationships between their inhibitory effects on carbonyl reduction, iron-chelation and antioxidant properties with respect to their protective potential against doxorubicin-induced cardiotoxicity. Cardioprotection was investigated in the neonatal rat ventricular cardiomyocytes whereas the H9c2 cardiomyoblast cells were used for cytotoxicity testing. Iron chelation was examined via the calcein assay and antioxidant effects and site-specific scavenging were quantified by means of inhibition of lipid peroxidation and hydroxyl radical scavenging activity, respectively. Inhibition of carbonyl reductases was assessed in cytosol from human liver. None of the flavonoids tested had better cardioprotective action than the reference cardioprotector, monoHER. However, a newly synthesized quaternary ammonium analog with comparable cardioprotective effects has been identified. No direct correlation between the iron-chelating and/or antioxidant effect and cardioprotective potential has been found. A major role of carbonyl reductase inhibition seems unlikely, as the best two cardioprotectors of the series are only weak reductase inhibitors.

Ameliorative Effect of Cardamom Aqueous Extract on Doxorubicin-Induced Cardiotoxicity in Rats

“…Moreover, DOX has a very high affinity to cardiolipin phospholipids that is normally present in cardiac mitochondrial membranes thereby leading to DOX accumulation in cardiac cells [Kaiserova et al, 2007]. DOX can also induce Ca 2+ ion overload in the myocardium which can activate phospholipase, leading to decomposition of membrane phospholipids [Kim et al, 2006].…”

“…The widely accepted mechanism to explain the role of DOX in ROS generation is an enzymatic-mediated pathway through conversion of the DOX quinine moiety to the corresponding DOX semiquinone form by NADH dehydrogenase and cytochrome P 450 reductase [Kalishina et al, 2003]. The molecular oxygen oxidizes the DOX semiquinone form to its quinine form with superoxide radical production [Kaiserova et al, 2007]. This redox reaction involves the reaction of Fe 3+ with DOX, where the iron atom gains an electron and the Fe 2+ -DOX free radical complex that reduces O 2 to H 2 O 2 and other active oxygen species [Kalishina et al, 2003].…”

Naringenin Enhances the Anti-Tumor Effect of Doxorubicin Through Selectively Inhibiting the Activity of Multidrug Resistance-Associated Proteins but not P-glycoprotein

“…Collected data demonstrate that the combinations of doxorubicin with flavonoids can enhance the sensitivity of tumor cells to doxorubicin (21) and reduce its cardiac toxicity (22,23). Naringenin (4′,5,7-trihydroxyflavanone),as one of the natural predominant flavonoids in citrus fruits, has been shown to inhibit the efflux of mitoxantrone, which is a substrate of BCRP (24).…”

Effect of Flavonoids on Daunorubicin‐induced Toxicity in H9c2 Cardiomyoblasts

“…Recently, it was found that flavonoids, powerful naturally occurring antioxidants, were able to reverse anthracycline-induced toxicity in rat cardiomyocytes (Mojzisová et al, 2006;Kaiserová et al, 2007). However, ethical consideration of animal protection and welfare, as well as practical considerations require that the use of laboratory animals should be limited as much as possible.…”