The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin.
The oral iron chelating agent ICL670A (deferasirox) and the clinically approved cardioprotective agent dexrazoxane (ICRF-187) were compared for their ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Doxorubicin is thought to induce oxidative stress on the heart muscle through iron-mediated oxygen radical damage. While dexrazoxane was able to protect myocytes from doxorubicin-induced lactate dehydrogenase release, ICL670A, in contrast, depending upon the concentration, synergistically increased or did not affect the cytotoxicity of doxorubicin. This occurred in spite of the fact that ICL670A quickly and efficiently removed iron(III) from its complex with doxorubicin, and rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. Continuous exposure of ICL670A to either myocytes or Chinese hamster ovary (CHO) cells resulted in cytotoxicity while treatment of CHO cells with the ferric complex of ICL670A did not. These results suggest that ICL670A was cytotoxic either by removing or withholding iron from critical iron-containing proteins. Electron paramagnetic resonance spectroscopy was used to show that neither ICL670A nor its ferric complex were able to generate free radicals in either oxidizing or reducing systems suggesting that its cytotoxicity is not due to radical generation.
Hasinoff
Brian B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada. B-Hasinoff@UManitoba.ca
Patel
Daywin
D
Wu
Xing
X
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D016466:CHO Cells; D002614:Chelating Agents / Q000494:pharmacology*; D006224:Cricetinae; D000077588:Deferasirox; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D007091:Image Processing, Computer-Assisted; D020287:In Situ Nick-End Labeling; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D032342:Muscle Cells / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D001565:Benzoates; D002614:Chelating Agents; D005609:Free Radicals; D014230:Triazoles; D004317:Doxorubicin; D007501:Iron; D007770:L-Lactate Dehydrogenase; D010100:Oxygen; D000077588:Deferasirox