Deferiprone protects against doxorubicin-induced myocyte cytotoxicity.
The iron chelating hydroxypyridinone deferiprone (CP20, L1) and the clinically approved cardioprotective agent dexrazoxane (ICRF-187) were examined for their ability to protect neonatal rat cardiac myocytes from doxorubicin-induced damage. Doxorubicin is thought to induce oxidative stress on the heart muscle, both through reductive activation to its semiquinone form, and by the production of hydroxyl radicals mediated by its complex with iron. The results of this study showed that both deferiprone and dexrazoxane were able to protect myocytes from doxorubicin-induced lactate dehydrogenase release. Deferiprone quickly and efficiently removed iron(III) from its complex with doxorubicin. In addition, this study also showed that deferiprone rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex, suggesting that in the myocyte, deferiprone should also be able to displace iron from its complex with doxorubicin. It was shown by electron paramagnetic resonance spectroscopy that under hypoxic conditions myocytes were able to reduce doxorubicin to its semiquinone free radical. Deferiprone also greatly reduced hydroxyl radical production by the iron(III)-doxorubicin complex in the xanthine oxidase/xanthine superoxide generating system. Together these results suggest that deferiprone may protect against doxorubicin-induced damage to myocytes by displacing iron bound to doxorubicin, or chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage.
Barnabé
Norman
N
Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, Canada.
Zastre
Jason A
JA
Venkataram
Suresh
S
Hasinoff
Brian B
BB
D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077543:Deferiprone; D004317:Doxorubicin / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D005452:Fluoresceins / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D007202:Indicators and Reagents / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000494:pharmacology
D000970:Antineoplastic Agents; D005452:Fluoresceins; D005609:Free Radicals; D007202:Indicators and Reagents; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D011929:Razoxane; D004317:Doxorubicin; D007501:Iron; D007770:L-Lactate Dehydrogenase; C007740:fluorexon