Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 103, Issue 7, Pages 1093-1101Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2009.05.007
Keywords
Dp44mT; Doxorubicin; Iron; Myocyte; Cardiotoxicity
Funding
- Canadian Institutes of Health Research
- Canada Research Chairs Program
- Canada Research Chair in Drug Development
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The iron chelating agent Dp44mT (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone) 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, in contrast Dp44mT synergistically increased doxorubicin-induced damage. This occurred in spite of the fact that Dp44mT quickly and efficiently removed iron(III) from its complex with doxorubicin and that Dp44mT also rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. Electron paramagnetic resonance spin trapping was used to show that iron complexes of Dp44mT were not able to generate hydroxyl radicals, Suggesting that its cytotoxicity was not due to reactive oxygen species formation. In conclusion Dp44mT is unlikely to be useful as an anthracycline cardioprotective agent. (C) 2009 Elsevier Inc. All rights reserved.
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