INVESTIGATION OF DRUG-INDUCED CARDIOTOXICITY IN PRECLINICAL MODELS: FOCUSING ON CARDIO-ONCOLOGY AND HIDDEN CARDIOTOXICITY
Gergely Tamás
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
NET Farmakológiai és Farmakoterápiás Intézet, Knoll (Issekutz) terem
2025-10-16 11:00:00
Experimental and Clinical Pharmacology
Dr. Szökő Éva
Dr. Varga Zoltán, Dr. Giricz Zoltán
Dr. Pozsonyi Zoltán
Dr. Czuriga Dániel
Dr. Geiszt Miklós
Dr.Molnár-Érsek Barbara
Dr. Kolossváry Márton
The field of drug-induced cardiotoxicity investigates cardiovascular adverse effects of both oncological and non-oncological drugs. Cardiotoxicity of anti-cancer medications often results from the main mechanism of the drug and cannot be uncoupled from the anti-cancer effect. The use of novel anti-cancer therapies with potential cardiotoxic effects, such as immune checkpoint inhibitors, is increasing, thus, an understanding of the cardiotoxic mechanisms is needed to develop cardioprotective therapies. On the other hand, the cardiotoxicity of non-oncological drugs should be recognized early during drug development via mandatory screening studies. Nevertheless, some cardiotoxic effects of drugs may only manifest in the diseased hearts, which is currently not tested during preclinical drug development, a phenomenon termed “hidden cardiotoxicity”. Thus, cardiovascular adverse effects may only be seen after market authorization in some cases.
In our first study, we investigated the mechanisms of anti-PD-1-induced cardiotoxicity in multiple mouse models. Immune checkpoint inhibitors are known to cause cardiotoxic effects, however, the mechanisms are incompletely understood. Here, we found that anti-PD-1 treatment induced significant cardiac dysfunction in C57BL/6J, but not in BALB/c mice. A mild inflammatory response was seen in the myocardium of the animals, however, a markedly increased pro-inflammatory gene expression was observed in the thymus of C57BL/6J mice. Of note, Il17a showed the highest upregulation. Thus, we targeted IL-17A with a neutralizing antibody, which prevented the development of cardiac dysfunction after anti-PD-1 treatment. These findings suggest that IL-17A may be a promising therapeutic target to alleviate ICI-induced cardiotoxicity.
In our second study, we investigated the potential hidden cardiotoxic effects of bempedoic acid, a novel antihyperlipidemic drug. Here, we used a rat model of acute cardiac ischemia/reperfusion injury as a model for hidden cardiotoxicity testing. We found that chronic pretreatment with bempedoic acid did not show hidden cardiotoxic properties in this model, on the contrary, it reduced the occurrence of reperfusion-induced arrhythmias. These results suggest that the use of bempedoic acid may be safe during cardiac ischemia/reperfusion injury.
