Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- DNA topoisomerases, type II, anthracyclines, cardiotoxicity, dexrazoxane,
- MeSH
- Anthracyclines adverse effects pharmacology MeSH
- Daunorubicin metabolism pharmacology MeSH
- Dexrazoxane adverse effects pharmacology MeSH
- DNA Topoisomerases, Type II adverse effects metabolism MeSH
- Topoisomerase II Inhibitors metabolism MeSH
- Myocytes, Cardiac drug effects metabolism MeSH
- Cardiotoxicity drug therapy metabolism prevention & control MeSH
- Humans MeSH
- Heart Diseases drug therapy MeSH
- Oxidative Stress drug effects MeSH
- Antibiotics, Antineoplastic adverse effects pharmacology MeSH
- Heart Failure drug therapy MeSH
- Check Tag
- Humans 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
- Topoisomerase II Inhibitors MeSH
- Antibiotics, Antineoplastic MeSH
BACKGROUND: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. METHODS: Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). RESULTS: Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; P<0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P<0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. CONCLUSIONS: This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.
Department of Pharmacology Faculty of Medicine in Hradec Králové Charles University Czech Republic
Department of Physiology Faculty of Medicine in Hradec Králové Charles University Czech Republic
References provided by Crossref.org
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