title: The antitumor anthracyclines doxorubicin and daunorubicin do not inhibit cell growth through the formation of iron-mediated reactive oxygen species.
abstract: The use of the anthracycline anticancer drugs doxorubicin and daunorubicin is limited by what is thought to be an iron-based oxygen radical-derived dose-dependent cardiotoxicity. The anthracyclines are also DNA topoisomerase (Topo) II poisons. It is not known if iron-mediated formation of reactive oxygen species (ROS) by the anthracyclines or their Topo II inhibitory effects are responsible for their cell growth-inhibitory effects. Experiments to test these two alternatives were carried out using a CHO-derived cell line (DZR) that was highly resistant to dexrazoxane through a Thr48IIe mutation in Topo IIalpha. The clinically used cardioprotective agent dexrazoxane likely exerts its cardioprotective effects through the chelating ability of its hydrolysis product ADR-925, an analog of EDTA. Dexrazoxane is also a cell growth inhibitor that acts through its ability to inhibit the catalytic activity of Topo II. Thus, the DZR cell line allowed us to examine the cell growth-inhibitory effects of doxorubicin and daunorubicin in the presence of dexrazoxane without the confounding effect of dexrazoxane inhibiting cell growth. The growth-inhibitory effects of neither doxorubicin nor daunorubicin were affected by pretreating DZR cells with dexrazoxane. In contrast, under similar conditions, dexrazoxane strongly protected rat cardiac myocytes from doxorubicin-induced lactate dehydrogenase release. In conclusion, the anthracyclines do not inhibit the growth of DZR cells through the generation of iron-mediated formation of ROS.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.forename: Brian B
authors.initials: BB
authors.lastname: Hasinoff
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D003630:Daunorubicin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D004317:Doxorubicin; D007501:Iron; D003630:Daunorubicin