Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation

Circ Heart Fail. 2021 Nov;14(11):e008209. doi: 10.1161/CIRCHEARTFAILURE.120.008209. Epub 2021 Sep 23.

Abstract

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.

Keywords: DNA topoisomerases, type II; anthracyclines; cardiotoxicity; dexrazoxane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracyclines / adverse effects
  • Anthracyclines / pharmacology*
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / pharmacology
  • Cardiotoxicity / drug therapy
  • Cardiotoxicity / metabolism
  • Cardiotoxicity / prevention & control*
  • DNA Topoisomerases, Type II / adverse effects
  • DNA Topoisomerases, Type II / metabolism
  • Daunorubicin / metabolism
  • Daunorubicin / pharmacology
  • Dexrazoxane / adverse effects
  • Dexrazoxane / pharmacology*
  • Heart Diseases / drug therapy
  • Heart Failure / drug therapy*
  • Humans
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Oxidative Stress / drug effects
  • Topoisomerase II Inhibitors / metabolism*

Substances

  • Anthracyclines
  • Antibiotics, Antineoplastic
  • Topoisomerase II Inhibitors
  • Dexrazoxane
  • DNA Topoisomerases, Type II
  • Daunorubicin