Improving the preclinical models for the study of chemotherapy-induced cardiotoxicity: a Position Paper of the Italian Working Group on Drug Cardiotoxicity and Cardioprotection

Abstract

Although treatment for heart failure induced by cancer therapy has improved in recent years, the prevalence of cardiomyopathy due to antineoplastic therapy remains significant worldwide. In addition to traditional mediators of myocardial damage, such as reactive oxygen species, new pathways and target cells should be considered responsible for the impairment of cardiac function during anticancer treatment. Accordingly, there is a need to develop novel therapeutic strategies to protect the heart from pharmacologic injury, and improve clinical outcomes in cancer patients. The development of novel protective therapies requires testing putative therapeutic strategies in appropriate animal models of chemotherapy-induced cardiomyopathy. This Position Paper of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to: (1) define the distinctive etiopatogenetic features of cardiac toxicity induced by cancer therapy in humans, which include new aspects of mitochondrial function and oxidative stress, neuregulin-1 modulation through the ErbB receptor family, angiogenesis inhibition, and cardiac stem cell depletion and/or dysfunction; (2) review the new, more promising therapeutic strategies for cardioprotection, aimed to increase the survival of patients with severe antineoplastic-induced cardiotoxicity; (3) recommend the distinctive pathological features of cardiotoxicity induced by cancer therapy in humans that should be present in animal models used to identify or to test new cardioprotective therapies.

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

“…Several mechanisms have been suggested to mediate DOXinduced toxicity to cardiomyocytes (4,25), whereas endothelial injury has received little attention (26,27). In our experiments, the apoptosis-associated DNA fragmentation was observed approximately to the same extent in cardiomyocytes and ECs.…”

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

“…In consideration of this novel premise, it must be taken into account that our investigation has limitations primarily that the mouse model may not truly reflect salient features of DOX‐induced cardiotoxicity in humans, because of differences in drug metabolism and/or cardiac structure and function, and sensitivity to cardiac injury, all of which may be influenced by ageing and co‐morbidities (Madonna et al, 2015). Preferentially, studies in human cardiac tissue would be performed, but being largely unobtainable, there has been increasing interest in disease modelling using human embryonic stem cell and induced pluripotent stem cell‐derived cardiomyocytes (Madonna et al, 2016; Maillet et al, 2016), although this also is not without criticism.…”

Current views on anthracycline cardiotoxicity

“…Top IIb is present in quiescent cells such as cardiomyocytes, and its inhibition by anthracyclines causes DNA double-strand breaks and transcriptome changes (responsible for defective mitochondrial biogenesis) and ROS formation [7]. Knowledge of the molecular mechanisms of anthracycline CTX is fundamental for understanding and selecting pharmacological [8] and non-pharmacological [9,10] strategies for CTX treatment and prevention.…”

“…The issues of cardioprotection and advanced heart failure therapy Old and novel promising pharmacological strategies for cardioprotection in patients treated with anthracyclines have recently been reviewed [8,92,93]. Unfortunately, despite a variety of studies in animal models, studies in humans are limited, generally small, and sometimes only retrospective.…”

“…Unfortunately, despite a variety of studies in animal models, studies in humans are limited, generally small, and sometimes only retrospective. Cardioprotective effects in patients have been shown for dexrazoxane, beta-blockers (carvedilol, nebivolol), angiotensin-converting-enzyme inhibitors (enalapril), angiotensin receptor blockers (valsartan, telmisartan), spironolactone, and statins (atorvastatin), which act at various molecular and cellular levels [8,92,93]. Dexrazoxane reduces the incidence of anthracyclineinduced HF by 80 % and is the only drug approved for its prevention [94].…”