The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin
The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin
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DOI：
10.1016/j.freeradbiomed.2003.08.005
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发表时间：
2003-12-01
影响因子：
7.4
通讯作者：
Wu, X
中科院分区：
文献类型：
--
作者：
Hasinoff, BB;Patel, D;Wu, X
比较口服铁螯合剂ICL670A（去铁氧铁）和临床批准的心脏保护剂dexrazoxane （ICRF-187）保护新生大鼠心肌细胞免受阿霉素诱导损伤的能力。阿霉素被认为通过铁介导的氧自由基损伤诱导心肌氧化应激。虽然dexrazoxane能够保护肌细胞免受阿霉素诱导的乳酸脱氢酶释放，但ICL670A相反，根据浓度的不同，协同增加或不影响阿霉素的细胞毒性。尽管ICL670A快速有效地从其与阿霉素的复合物中去除铁（III），并迅速进入肌细胞，并从荧光淬灭的细胞内铁钙黄蛋白复合物中置换铁，但仍发生了这种情况。ICL670A持续暴露于肌细胞或中国仓鼠卵巢（CHO）细胞导致细胞毒性，而ICL670A的铁络合物处理CHO细胞则没有细胞毒性。这些结果表明，ICL670A通过去除或抑制关键含铁蛋白中的铁而具有细胞毒性。电子顺磁共振波谱显示，ICL670A及其铁配合物在氧化或还原系统中均不能产生自由基，表明其细胞毒性不是由于自由基的产生。(C) 2003 Elsevier Inc.
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. (C) 2003 Elsevier Inc.