Book of Abstracts - New Frontiers 2022

Abstracts of poster presentations

ROLE OF PHARMACOLOGICAL INHIBITION OF ATM IN THE DEVELOPMENT OF ANTHRACYCLINE CARDIOTOXICITY

O. Lenčová 1 , P. Kollárová 2 , M. Adamcová 2 , Y. Mazurová 3 , M. Štěrba 3

1 Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; 2 Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic; 3 Department of Histology and Embryology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic Anthracycline (ANT) cardiotoxicity resulting in cardiomyopathy and heart failure is still the main limitation of the clinical use of ANT anticancer drugs. Many mechanisms have been suggested to be involved in ANT induced cardiac damage, but topoisomerase II beta (TOP2B)-dependent DNA damage in cardiomyocytes has become one of the leading theories. However, DNA damage response (DDR) downstream of TOP2B poisoning and its role in the pathogenesis of ANT cardiotoxicity remains elusive. This study aimed to use pharmacological inhibition of ATM to clarify whether this pathway is involved in DDR signaling in the heart after ANT exposure and whether the ATM-orchestrated signaling leads to the development of ANT cardiotoxicity or the opposite is true. For this purpose, chronic cardiotoxicity was induced in male rabbits by daunorubicin (DAU, 3 mg/kg, weekly for ten weeks). The highly selective and potent ATM inhibitor AZD0156, which is currently in clinical evaluation, was administered at a dose of 0.5 mg/kg either alone or 30 min before each dose of DAU. The results were compared with groups receiving saline or vehicle for AZD0156. In another set of animals, the DDR in the heart was studied 6 hours after a single administration of the same drugs. Our results show that ATM inhibitor AZD0156 effectively prevented the acute DAU induced increase of p53 levels and up-regulation of p53 target genes (p21 and many others) in the left ventricular (LV) myocardium. Furthermore, chronic co-treatment of rabbits with AZD0156 and DAU resulted in markedly increased severity of cardiotoxicity and end-stage congestive heart failure as compared to DAU alone. This finding was documented by a markedly increased incidence of DAU-induced blood congestion (hydrothorax 80 % vs. 40 % in the DAU-alone group), heart failure-related mortality (60 % vs. 20 % in the DAU-alone group), steep rise in plasma levels of cardiac troponin T before the observed deaths and profound decrease in LV fractional shortening (LVFS) determined by echocardiography. The last measured LVFS values in the AZD0156+DAU group were significantly lower than in the DAU-alone group. AZD0156 alone was well tolerated and had no significant impact on any studied parameter. In summary, it seems that ANT-induced DDR signaling in the heart appears to be ATM-dependent, and pharmacological inhibition of ATMmay sensitize rabbit hearts to the development of ANT-induced chronic cardiotoxicity and heart failure.

Keywords: Anthracyclines; cardiotoxicity; DNA damage signaling; ATM; pharmacological modulation

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.

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