Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury.
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.
Faculty of Pharmacy in Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
Petra
P
Bendova
Eliska
E
Mackova
Pavlina
P
Haskova
Anna
A
Vavrova
Eduard
E
Jirkovsky
Martin
M
Sterba
Olga
O
Popelova
Danuta S
DS
Kalinowski
Petra
P
Kovarikova
Katerina
K
Vavrova
Des R
DR
Richardson
Tomas
T
Simunek
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects*; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D007502:Iron Chelating Agents; D020122:tert-Butylhydroperoxide