Huang M-F, Pang LK, Chen Y-H, Zhao R, and Lee D-F.
Cells, 2021.
The iPSC-CM model allows scientists to uncover underlying mechanisms of cardiotoxicity, assess drug safety and ideal dosing, and discover therapies to counteract the toxic effects of anticancer agents on the heart.
Cardiotoxicity is associated with many classes of anticancer drugs including anthracyclines, anti-microtubule agents, tyrosine kinase inhibitors, and antibody-based drugs, but the underlying mechanisms of cardiotoxicity are not well understood. Although robust research into antineoplastic agents using mouse models, autologous cells, and human embryonic stem cells is plentiful, these platforms are limited by substantial biological differences between humans and animals, difficulty extracting and maintaining cells, and ethical concerns, respectively.
However, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a promising platform for the study of cardiotoxicity due to their unlimited supply, stable cell culture, and ability to capture unique genetic signatures. Additionally, iPSC-CMs have the ability to mimic in vivo cardiomyocytes, possessing cardiac-specific ion channels, a dynamic contractile apparatus, calcium-handling properties, and spontaneous beats.
To illustrate the significance of iPSC-CMs in assessing cardiotoxicity, the authors of this review examine studies using the model to investigate links between anticancer agents and cardiac conditions including arrythmia, hypertension, acute ischemia, myocarditis, congestive heart failure, impaired ejection fraction, and others. In one such study, scientists used Axion’s Maestro MEA platform and other testing to investigate the molecular mechanisms of doxorubicin and found that the drug causes dose-dependent increases in apoptotic and necrotic cell death, reactive oxygen species production, mitochondrial dysfunction, and increased intracellular calcium concentration. Using the iPSC-CM model, researchers were also able to demonstrate a critical role of TOP2β in doxorubicin-induced cardiotoxicity. The authors conclude that the similarities between iPSC-CMs and physiological cardiomyocytes will allow scientists to broaden their understanding of the mechanisms underlying cardiotoxicity from antineoplastic agents in ways that were once thought impossible, screen agents for cardiotoxicity, determine ideal dosing, and discover therapies to counteract the toxic effects of anticancer agents on the heart.
