Comparison of Clinically Used and Experimental Iron Chelators for Protection against Oxidative Stress-Induced Cellular Injury

Abstract

Iron imbalance plays an important role in oxidative stress associated with numerous pathological conditions. Therefore, iron chelation may be an effective therapeutic approach, but progress in this area is hindered by the lack of effective ligands. Also, the potential favorable effects of chelators against oxidative injury have to be balanced against their own toxicity due to iron depletion and the ability to generate redox-active iron complexes. In this study, we compared selected iron chelators (both drugs used in clinical practice as well as experimental agents) for their efficacy to protect cells against model oxidative injury induced by tert-butyl hydroperoxide (t-BHP). In addition, intracellular chelation efficiency, redox activity, and the cytotoxicity of the chelators and their iron complexes were assayed. Ethylenediaminetetraacetic acid failed to protect cells against t-BHP cytotoxicity, apparently due to the redox activity of the formed iron complex. Hydrophilic desferrioxamine exerted some protection but only at very high clinically unachievable concentrations. The smaller and more lipophilic chelators, deferiprone, deferasirox, and pyridoxal isonicotinoyl hydrazone, were markedly more effective at preventing oxidative injury of cells. The most effective chelator in terms of access to the intracellular labile iron pool was di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone. However, overall, the most favorable properties in terms of protective efficiency against t-BHP and the chelator's own inherent cytotoxicity were observed with salicylaldehyde isonicotinoyl hydrazone. This probably relates to the optimal lipophilicity of this latter agent and its ability to generate iron complexes that do not induce marked redox activity.

The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action

“…For these latter ligands, this effect could lead to tumor cytotoxicity due to the redox activity of these complexes (Whitnall et al, 2006;Yu et al, 2011a). However, this could not explain the antitumor efficacy of deferasirox, as its iron complex is not redox-active (Bendová et al, 2010;Ha sková et al, 2011).…”

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

“…Therefore, we chose to administer deferasirox, a relatively new iron chelator that can be administered orally at once, has a good bioavailability of approximately 70%, with peak plasma levels between 2 and 4 h after ingestion, 27 and has been shown to protect against oxidative stress-induced damage in patients. [28][29][30][31] We chose a relatively high dosage of 30 mg/kg. 32 Although deferasirox has roughly the same characteristics as deferrioxamin with regard to the chelation of iron, there might be a difference in anti-oxidative capacity between the two compounds.…”

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

“…L1 protected neurons as well as fibroblasts against H 2 O 2 -induced cell death in vitro (165,189). It also protected an H9c2 cardiomyoblastderived cell line against model oxidative injury induced by tert-butyl hydroperoxide (15) and rat hearts against the ischemia-reperfusion injury (276). Two in vitro studies demonstrated that treatment with L1 resulted in an inhibition of DOX (0.6-1.8 lM) toxicity in both iron-loaded and normal cardiac culture cells (10,166).…”

“…Furthermore, a short plasma halflife of DFO may also reduce its potential. In fact, numerous previous studies have demonstrated that DFO is clearly inferior in protecting cardiac cells from oxidative stressinducing agents as compared to smaller and more lipophilic ligands (15,93,188,238), and therefore during the last years, the research interest shifted in this direction.…”

“…It is a synthetic triazole chelator that has been also shown capable to remove cardiac iron and attenuate myocardial oxidative stress in the state of iron overload (4). It has been shown as capable to protect H9c2 cells from tert-butyl hydroperoxide (15), significantly retard the spontaneous catecholamine oxidation, block the intracellular ROS formation, and exert significant protection against the cellular toxicity of catecholamines and their oxidation products with very low (3 lM) effective concentrations (93). ICL670A, tested in the same in vitro model as the L1, did not protect isolated rat cardiomyocytes against DOX (89).…”