Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

Abstract

Purpose of review: Both traditional and novel cancer therapies can cause cardiovascular toxicity in patients. In vivo models integrating both cardiovascular and cancer phenotypes allow for the study of on- and off-target mechanisms of toxicity arising from these agents. The zebrafish is the optimal whole organism model to screen for cardiotoxicity in a high throughput manner, while simultaneously assessing the role of cardiotoxicity pathways on the cancer therapy’s antitumor effect. Here we highlight established zebrafish models of human cardiovascular disease and cancer, the unique advantages of zebrafish to study mechanisms of cancer therapy-associated cardiovascular toxicity, and finally, important limitations to consider when using the zebrafish to study toxicity. Recent findings: Cancer therapy-associated cardiovascular toxicities range from cardiomyopathy with traditional agents to arrhythmias and thrombotic complications associated with newer targeted therapies. The zebrafish can be used to identify novel therapeutic strategies that selectively protect the heart from cancer therapy without affecting antitumor activity. Advances in genome editing technology have enabled the creation of several transgenic zebrafish lines valuable to the study of cardiovascular and cancer pathophysiology. Summary: The high degree of genetic conservation between zebrafish and humans, as well as the ability to recapitulate cardiotoxic phenotypes observed in patients with cancer, make the zebrafish an effective model to study cancer therapy-associated cardiovascular toxicity. Though this model provides several key benefits over existing in vitro and in vivo models, limitations of the zebrafish model include the early developmental stage required for most high-throughput applications.

Optical transparency and label-free vessel imaging of zebrafish larvae in shortwave infrared range as a tool for prolonged studying of cardiovascular system development

“…Transparent zebrafish larvae are also widely used for the assessment of drug-induced cardiotoxicity 45 . This kind of toxicity is one of the most frequent reasons for drug withdrawals 46 .…”

Cardio-Oncology Preclinical Models: A Comprehensive Review

“…Moreover, zebrafish cardiomyocytes express voltage-gated sodium channels, Ltype and T-type calcium channels and potassium channel, similarly to vertebrates (67). These electrophysiological characteristics of zebrafish model are useful to study drugassociated QT prologation (68). Furthremore, with the advances in genome editing technology, transgenic zebrafish models were developed.…”

“…Moreover, a study that used a genetically modified mouse model to identify the molecular basis of radiation-induced cardiotoxicity demonstrated that p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice (72). In another study, in which female rats received a 24 Gy localized whole-heart radiation, myocardial strain worsened post-RT, especially at 10-weeks and in lateral regions (68). Combined radiation therapy and antineoplastic drugs have been little studied through animal models.…”

“…Genetically modified animals allow a better understanding of the mechanisms of cardiotoxicity induced by antineoplastic treatments. The zebrafish has emerged as a promising model due to its high degree of similarity with human cardiovascular function (68). More studies are needed to validate these models in the cardio-oncology field.…”

Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure

“…Due to its amenability to high-throughput genetic and compound screening, zebrafish (Danio rerio) has emerged as a highly prolific vertebrate animal model to study human cardiac diseases [7][8][9]. Surprisingly, many cardiac electrophysiological behaviors of zebrafish have higher conservation than mouse with humans [7].…”