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

BACKGROUND: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions. METHODS: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection. RESULTS: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation. CONCLUSION: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

• MeSH
• Anthracyclines antagonists & inhibitors   toxicity   MeSH
• Apoptosis drug effects   MeSH
• Myocytes, Cardiac cytology   drug effects   MeSH
• Cardiotonic Agents pharmacology   MeSH
• Cardiotoxins antagonists & inhibitors   toxicity   MeSH
• Rabbits MeSH
• Heart Diseases chemically induced   pathology   prevention & control   MeSH
• Razoxane pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anthracyclines MeSH
• Cardiotonic Agents MeSH
• Cardiotoxins MeSH
• Razoxane MeSH

BACKGROUND AND PURPOSE: The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS). EXPERIMENTAL APPROACH: The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation. KEY RESULTS: SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

• MeSH
• Leukemia, Promyelocytic, Acute metabolism   pathology   MeSH
• Aldehydes pharmacology   MeSH
• Time Factors MeSH
• Iron Chelating Agents pharmacology   MeSH
• Cytoprotection MeSH
• Daunorubicin toxicity   MeSH
• HL-60 Cells MeSH
• Hydrazones pharmacology   MeSH
• Myocytes, Cardiac drug effects   metabolism   pathology   MeSH
• Rats MeSH
• Humans MeSH
• Malondialdehyde metabolism   MeSH
• Animals, Newborn MeSH
• Oxidative Stress drug effects   MeSH
• Lipid Peroxidation drug effects   MeSH
• Rats, Wistar MeSH
• Cell Proliferation drug effects   MeSH
• Antibiotics, Antineoplastic toxicity   MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug 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
• Aldehydes MeSH
• Iron Chelating Agents MeSH
• Daunorubicin MeSH
• Hydrazones MeSH
• Malondialdehyde MeSH
• Antibiotics, Antineoplastic MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser

BACKGROUND AND PURPOSE: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stress-mediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. EXPERIMENTAL APPROACH: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H(2)O(2)) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay. KEY RESULTS: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H(2)O(2)/Fe(2+) in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H(2)O(2)/Fe(2+). Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H(2)O(2)/Fe(2+). CONCLUSIONS AND IMPLICATIONS: We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.

• MeSH
• Aldehydes pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Bleomycin toxicity   MeSH
• Time Factors MeSH
• Iron Chelating Agents chemistry   pharmacology   MeSH
• Deferoxamine pharmacology   MeSH
• Doxorubicin toxicity   MeSH
• Electron Spin Resonance Spectroscopy MeSH
• Hydrazones pharmacology   MeSH
• Isoniazid analogs & derivatives   pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Lung Neoplasms metabolism   pathology   MeSH
• Oxidative Stress drug effects   MeSH
• Hydrogen Peroxide chemistry   MeSH
• Lipid Peroxidation drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antibiotics, Antineoplastic toxicity   MeSH
• Pyridoxal analogs & derivatives   pharmacology   MeSH
• Razoxane pharmacology   MeSH
• Iron Compounds chemistry   metabolism   MeSH
• Cell Survival drug effects   MeSH
• Free Radicals chemistry   MeSH
• Iron chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehydes MeSH
• Bleomycin MeSH
• Iron Chelating Agents MeSH
• Deferoxamine MeSH
• Doxorubicin MeSH
• Fenton's reagent MeSH Browser
• Hydrazones MeSH
• Isoniazid MeSH
• Hydrogen Peroxide MeSH
• Antibiotics, Antineoplastic MeSH
• pyridoxal isonicotinoyl hydrazone MeSH Browser
• Pyridoxal MeSH
• Razoxane MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Iron Compounds MeSH
• Free Radicals MeSH
• Iron MeSH