Use of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes in Preclinical Cancer Drug Cardiotoxicity Testing: A Scientific Statement From the American Heart Association

It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced quality of life. These effects, which may manifest in the short term or long term, are mechanistically not well understood. Research is hampered by the reliance on whole-animal models of cardiotoxicity that may fail to reflect the fundamental biology or cardiotoxic responses of the human myocardium. The emergence of human induced pluripotent stem cell–derived cardiomyocytes as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity of oncological drugs that may manifest as contractile and electrophysiological dysfunction, as well as structural abnormalities, making it possible to deliver novel drugs free from cardiac liabilities and guide personalized therapy. This article briefly reviews the challenges of cardio-oncology, the strengths and limitations of using human induced pluripotent stem cell–derived cardiomyocytes to represent clinical findings in the nonclinical research space, and future directions for their further use.

Download Full-text

Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2019.114761 ◽

2019 ◽

Vol 383 ◽

pp. 114761

Author(s):

Toshikatsu Matsui ◽

Kazumasa Miyamoto ◽

Kazunori Yamanaka ◽

Yoshiko Okai ◽

Emily Pfeiffer Kaushik ◽

...

Keyword(s):

Stem Cell ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Assessment System ◽

Cancer Drug ◽

Two Dimensional ◽

Drug Induced ◽

Induced Pluripotent ◽

Morphological Assessment

Download Full-text

Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes

eLife ◽

10.7554/elife.68714 ◽

2021 ◽

Vol 10 ◽

Author(s):

Francis Grafton ◽

Jaclyn Ho ◽

Sara Ranjbarvaziri ◽

Farshad Farshidfar ◽

Anastasiia Budan ◽

...

Keyword(s):

Stem Cell ◽

Deep Learning ◽

Pluripotent Stem Cell ◽

Kinase Inhibitors ◽

Early Stage ◽

Induced Pluripotent Stem Cell ◽

Channel Blockers ◽

Drug Induced ◽

Induced Pluripotent

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.

Download Full-text