Abstract P3116: Cardioprotective Effects Of Dexrazoxane Derivatives Against Chronic Anthracycline Cardiotoxicity Depend On Topoisomerase II Beta Inhibition And Prevention Of DNA Damage Signaling In The Heart

• Published in: Circulation research 2022-08, Vol.131 (Suppl_1), p.AP3116-AP3116
• Main Authors: Kollarova, Petra, Lencova, Olga, Karabanovich, Galina, Kubes, Jan, Vanova, Nela, Roh, Jaroslav, Simunek, Tomas, Sterbova, Petra, Sterba, Martin
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3116

BackgroundCardioprotective effects of dexrazoxane (DEX), the only drug approved against anthracycline (ANT) cardiotoxicity, have been traditionally associated with metal chelating properties of its metabolites. However, newer data point to importance of interaction of the parent drug with topoisomerase II beta (TOP2B). HypothesisClose derivatives of DEX with different ability to catalytically inhibit TOP2B will show different capability to prevent ANT-induced and TOP2B-depedent DNA damage signaling in the heart which will determine their different cardioprotective effects against chronic ANT cardiotoxicity in vivo. MethodsChronic ANT cardiotoxicity was induced with daunorubicin (DAU, 3 mg/kg/week for 10 weeks). DEX and its N,N′-dimethyl derivative were administered at 60 mg/kg, while a water-soluble prodrug of DEX derivative with additional methyl on the aliphatic linker (ICRF-193) was administered at 1 or 5 mg/kg. All drugs were administered 30 min before each DAU dose, and the results were compared with the appropriate control groups. ResultsDEX co-treatment almost completely prevented all DAU-induced markers of chronic cardiotoxicity including heart failure-related mortality, left ventricular dysfunction and cardiac troponin T raise in plasma. However, its dimethyl derivative failed to show any cardioprotective potential as all results were not different from the DAU-alone group despite even higher plasma concentrations of the parent compound as well as the main metabolite (compared with DEX). In contrast, the prodrug of ICRF-193 showed dose-dependent cardioprotection with almost complete protection in all studied parameters at 5 mg/kg, despite much lower plasma concentrations of the active derivative ICRF-193. The ability to protect heart against chronic ANT cardiotoxicity correlated with the potency of studied drugs to catalytically inhibit TOP2B in vitro and capability to prevent acute DAU-induced and p53-mediated DNA damage signaling in the heart in vivo. ConclusionCardioprotective effects of DEX derivatives against chronic ANT cardiotoxicity in vivo are closely related to their ability to catalytically inhibit TOP2B and prevent ANT-induced DNA damage signaling in the heart.