title: Catalytic inhibitors of topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells.
abstract: Anthracyclines (such as doxorubicin or daunorubicin) are among the most effective anticancer drugs, but their usefulness is hampered by the risk of irreversible cardiotoxicity. Dexrazoxane (ICRF-187) is the only clinically approved cardioprotective agent against anthracycline cardiotoxicity. Its activity has traditionally been attributed to the iron-chelating effects of its metabolite with subsequent protection from oxidative stress. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2). Therefore, we examined whether dexrazoxane and two other TOP2 catalytic inhibitors, namely sobuzoxane (MST-16) and merbarone, protect cardiomyocytes from anthracycline toxicity and assessed their effects on anthracycline antineoplastic efficacy. Dexrazoxane and two other TOP2 inhibitors protected isolated neonatal rat cardiomyocytes against toxicity induced by both doxorubicin and daunorubicin. However, none of the TOP2 inhibitors significantly protected cardiomyocytes in a model of hydrogen peroxide-induced oxidative injury. In contrast, the catalytic inhibitors did not compromise the antiproliferative effects of the anthracyclines in the HL-60 leukemic cell line; instead, synergistic interactions were mostly observed. Additionally, anthracycline-induced caspase activation was differentially modulated by the TOP2 inhibitors in cardiac and cancer cells. Whereas dexrazoxane was upon hydrolysis able to significantly chelate intracellular labile iron ions, no such effect was noted for either sobuzoxane or merbarone. In conclusion, our data indicate that dexrazoxane may protect cardiomyocytes via its catalytic TOP2 inhibitory activity rather than iron-chelation activity. The differential expression and/or regulation of TOP2 isoforms in cardiac and cancer cells by catalytic inhibitors may be responsible for the selective modulation of anthracycline action observed.
authors.affiliation: Department of Biochemical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Vavrova
authors.forename: Hana
authors.initials: H
authors.lastname: Jansova
authors.forename: Eliska
authors.initials: E
authors.lastname: Mackova
authors.forename: Miloslav
authors.initials: M
authors.lastname: Machacek
authors.forename: Pavlina
authors.initials: P
authors.lastname: Haskova
authors.forename: Lucie
authors.initials: L
authors.lastname: Tichotova
authors.forename: Martin
authors.initials: M
authors.lastname: Sterba
authors.forename: Tomas
authors.initials: T
authors.lastname: Simunek
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018943:Anthracyclines / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology; D064730:Dexrazoxane / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013858:Thiobarbiturates / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D018943:Anthracyclines; D010879:Piperazines; D013858:Thiobarbiturates; D059005:Topoisomerase II Inhibitors; D064730:Dexrazoxane; D004317:Doxorubicin; D020169:Caspases; D004250:DNA Topoisomerases, Type II; D005978:Glutathione; C057773:sobuzoxane; D019803:Glutathione Disulfide; C045459:merbarone; D003630:Daunorubicin