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.

• MeSH
• antracykliny farmakologie   MeSH
• biokatalýza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• daunomycin farmakologie   MeSH
• dexrazoxan farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• doxorubicin farmakologie   MeSH
• glutathion metabolismus   MeSH
• glutathiondisulfid metabolismus   MeSH
• HL-60 buňky MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• kardiomyocyty cytologie   účinky léků   metabolismus   MeSH
• kaspasy metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• novorozená zvířata MeSH
• piperaziny farmakologie   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• thiobarbituráty farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• daunomycin MeSH
• dexrazoxan MeSH
• DNA-topoisomerasy typu II MeSH
• doxorubicin MeSH
• glutathion MeSH
• glutathiondisulfid MeSH
• inhibitory topoisomerasy II MeSH
• kaspasy MeSH
• merbarone MeSH Prohlížeč
• piperaziny MeSH
• sobuzoxane MeSH Prohlížeč
• thiobarbituráty MeSH