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
• Anthracyclines pharmacology   MeSH
• Biocatalysis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Daunorubicin pharmacology   MeSH
• Dexrazoxane pharmacology   MeSH
• DNA Topoisomerases, Type II metabolism   MeSH
• Doxorubicin pharmacology   MeSH
• Glutathione metabolism   MeSH
• Glutathione Disulfide metabolism   MeSH
• HL-60 Cells MeSH
• Topoisomerase II Inhibitors pharmacology   MeSH
• Myocytes, Cardiac cytology   drug effects   metabolism   MeSH
• Caspases metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Drug Interactions MeSH
• Humans MeSH
• Animals, Newborn MeSH
• Piperazines pharmacology   MeSH
• Rats, Wistar MeSH
• Cell Proliferation drug effects   MeSH
• Flow Cytometry MeSH
• Thiobarbiturates pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anthracyclines MeSH
• Daunorubicin MeSH
• Dexrazoxane MeSH
• DNA Topoisomerases, Type II MeSH
• Doxorubicin MeSH
• Glutathione MeSH
• Glutathione Disulfide MeSH
• Topoisomerase II Inhibitors MeSH
• Caspases MeSH
• merbarone MeSH Browser
• Piperazines MeSH
• sobuzoxane MeSH Browser
• Thiobarbiturates MeSH

SIGNIFICANCE: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. RECENT ADVANCES: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. CRITICAL ISSUES: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. FUTURE DIRECTIONS: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

• MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Anthracyclines adverse effects   chemistry   pharmacology   MeSH
• Chelating Agents adverse effects   chemistry   pharmacology   MeSH
• Cardiotonic Agents adverse effects   chemistry   pharmacology   MeSH
• Metals adverse effects   MeSH
• Humans MeSH
• Myocardium metabolism   MeSH
• Oxidation-Reduction MeSH
• Oxidative Stress * MeSH
• Antineoplastic Agents adverse effects   chemistry   pharmacology   MeSH
• Razoxane adverse effects   chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Signal Transduction * MeSH
• Heart drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH
• Anthracyclines MeSH
• Chelating Agents MeSH
• Cardiotonic Agents MeSH
• Metals MeSH
• Antineoplastic Agents MeSH
• Razoxane MeSH
• Reactive Oxygen Species MeSH