The iron chelator Dp44mT does not protect myocytes against doxorubicin.
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.
Hasinoff
Brian B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada. B_Hasinoff@UManitoba.ca
Patel
Daywin
D
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D019610:Cytoprotection; D004317:Doxorubicin / Q000633:toxicity*; D005029:Ethylenediamines / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000737:chemistry / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D005029:Ethylenediamines; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones; D011929:Razoxane; C059866:ICRF 198; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D005998:Glycine