Deferiprone protects against doxorubicin-induced myocyte cytotoxicity

被引:76
作者
Barnabé, N [1 ]
Zastre, JA [1 ]
Venkataram, S [1 ]
Hasinoff, BB [1 ]
机构
[1] Univ Manitoba, Fac Pharm, Winnipeg, MB R3T 2N2, Canada
基金
加拿大健康研究院;
关键词
deferiprone; antioxidant; doxorubicin; iron; myocyte; cardiotoxicity; EPR; semiquinone; calcein; free radicals;
D O I
10.1016/S0891-5849(02)00873-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2002 Elsevier Science Inc.
引用
收藏
页码:266 / 275
页数:10
相关论文
共 44 条