Book of Abstracts - New Frontiers 2022

Abstracts of poster presentations

A NEW BISDIOXOPIPERAZINE ANALOGUE PROVIDES PROMISING PROTECTIVE EFFECTS AGAINST CHRONIC ANTHRACYCLINE CARDIOTOXICITY IN VIVO IN RABBITS

P. Kollárová 1 , O. Lenčová 1 , G. Karabanovich 2 , J. Kubeš 2 , Y. Mazurová 1 , M. Adamcová 1 , A. Jirkovská 2 , T. Šimůnek 2 , J. Roh 2 , M. Štěrba 1 1 Charles University, Faculty of Medicine, Hradec Králové, Czech Republic; 2 Charles University, Faculty of Pharmacy, Hradec Králové, Czech Republic Chronic anthracycline (ANT) cardiotoxicity manifesting itself as heart failure is a feared complication of cancer chemotherapy. The only drug approved for its prevention is a bisdioxopiperazine agent dexrazoxane (DEX). Although its mechanism of action is still incompletely understood, the recent findings suggest the key role of catalytic inhibition of topoisomeras e IIβ (TOP2B) which should prevent ANT -induced DNA damage caused by poisoning of the enzyme. We and others have studied dozens of DEX derivatives, but only a close derivative of DEX (ICRF-193) appeared more effective than DEX in vitro. However, poor water solubility of ICFR-193 precluded its testing beyond in vitro level and thus its prodrug (compound GK-667) was synthesized and selected for in vivo examination. The aim of this study was to investigate whether compound GK-667 can provide effective and dose dependent cardioprotection against chronic ANT cardiotoxicity in a DEX-validated in vivo model. Furthermore, molecular aspects of cardiotoxicity and cardioprotection were investigated. The cardiotoxicity was induced in rabbits by daunorubicin (DAU, 3 mg/kg, i.v., weekly for 10 weeks, n=10) and GK-667 (1 or 5 mg/kg, i.v., n=10 in each group) was administered 30 min before each DAU dose in the combination groups. Other groups received GK-667 alone (5 mg/kg, n=7) and saline (n=10). At the end of the study, cardiac troponin T was analysed in plasma and cardiac function was assessed by echocardiography and left ventricular (LV) catheterization. Administration of DAU resulted in 20% mortality, blood congestion in about one third of the animals and significant systolic dysfunction as examined by both echocardiography and LV catheterization. All these events were completely prevented by co-treatment with both doses of GK-667. Dose dependency of cardioprotective effects of GK-667 was notable on molecular markers of cardiac damage and dysfunction – particularly cardiac troponin T in plasma and expression of ANP in the LV myocardium. Chronic DAU treatment also induced p53-mediated DNA damage response (DDR) which was also found dose dependently preventable by GK-667 co-treatment. Moreover, DAU induced a marked acute DDR even after single dose, and even here GK-667 induced dose-dependent prevention. Interestingly, another close DEX derivative, which has been previously found ineffective as both TOP2B inhibitor and cardioprotectant, was unable to affect the acute DAU-induced DDR in the heart. In conclusion, these results suggest that GK-667 is to the best of our knowledge the most potent bisdioxopiperazine cardioprotective agent against chronic ANT cardiotoxicity. Its cardioprotective effects can be attributed to the prevention of DAU-induced and p53 mediated DNA damage response in the heart via catalytic inhibition of TOP2B by ICRF-193 released from the prodrug. Overall, GK-667 is an interesting drug candidate for further research and development.

Keywords: anthracycline, cardiotoxicity, cardioprotection, dexrazoxane, ICRF-193

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.

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