Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

PHARMACOLOGICAL CARDIOPROTECTION AGAINST CHRONIC ANT CARDIOTOXICITY – TOPOISOMERASE II BETA TARGETING AND BEYOND

M. Štěrba

Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Králové, Czech Republic

Anthracycline (ANT) cardiotoxicity resulting in cardiomyopathy and heart failure continues to be a significant issue for current clinical cardio-oncology. The only drug approved for protection of the heart against ANT toxicity is a bisdioxopiperazine derivative dexrazoxane (DEX). It has long been believed to act through metal chelating effects of its metabolite, which should prevent iron-catalyzed oxidative stress, but recently published data from our laboratory has refuted this hypothesis using direct experimental evidence. We have shown instead that the parent DEX molecule acts as a catalytic inhibitor of topoisomerase II beta (TOP2B), which prevents poisoning of the enzyme by ANTs in the cardiomyocytes and thereby overcomes ANT-induced DNA damage and DNA damage signaling in the heart. The validity of the TOP2B hypothesis has been supported by our numerous in vitro and in vivo experiments with DEX and its derivatives. The DEX derivatives, which were ineffective as catalytic inhibitors of TOP2B, lacked a cardioprotective potential in the chronic cardiotoxicity model despite even very minor changes in chemical structure and preserved iron chelating activity. Bisdioxopiperazine derivatives, more potent than DEX as TOP2B catalytic inhibitors, were also more potent as cardioprotectants. These cardioprotective effects correlated closely with the ability of these DEX derivatives to prevent p53-mediated DNA damage response (DDR) signaling in the heart induced by a single clinically relevant ANT dose. Furthermore, we have demonstrated that ACE inhibitors, which do not prevent TOP2B-dependent and p53-mediated DDR, can provide only temporal, but not long-lasting cardioprotection against chronic ANT cardiotoxicity, which contrasted with effects obtained with DEX on the same model. In addition, we observed that a selective inhibition of ATM, a key molecule located at the apex of DDR, can also blunt the ANT-induced DDR signaling in the heart. However, the addition of the ATM inhibitor to the chronic ANT treatment had an opposite impact on the ANT cardiotoxicity development than DEX – it augmented the severity of ANT induced cardiotoxicity in the same experimental model. In conclusion, while the catalytic inhibition of TOP2B with DEX and its derivatives is a promising cardioprotective strategy, the ATM inhibition blocking downstream DDR signaling seems to have a rather detrimental impact on chronic ANT cardiotoxicity development.

Keywords: Cardiotoxicity, cardioprotection, topoisomerase II beta, DNA damage response, anthracyclines

Funding:This work was supported by the Project InoMed CZ.02.1.01/0.0/0.0/18 069/0010046 co funded by the ERDF and the project GAČR No. 21 -16195S.

56