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Studies on Prediction of Cardiotoxicity Induced by Anticancer Drugs and Exploration of Molecular Targets to Prevent Cardiotoxicity

松井, 俊勝 筑波大学 DOI:10.15068/0002008141

2023.09.04

概要

The discovery of human stem cells and subsequent establishment of methods for their differentiation
into various lineages have provided a solid basis for toxicity evaluations. In the past several years,
human iPSC-CMs have widely been used to predict in vivo cardiotoxicity (Pointon et al., 2013;Doherty
et al., 2015;Sharma et al., 2017). To date, QT prolongation and arrhythmia-related indicators have
been evaluated extensively by an electrophysiological approach (Ma et al., 2011). However, few
studies have examined the drug-induced heart failure caused by a sustained contractile dysfunction,
mainly owing to the lack of an appropriate device for measuring cardiac contractility in vitro. Indeed,
the main currently available method to evaluate drug-induced alterations of cardiac contractility
involves an isolated perfused heart obtained from rodents in most cases (Anderson et al., 1990).
However, this method is time-consuming and labor-intensive, and is thus not suitable for screening
large numbers of compounds. To overcome this limitation, I focused on evaluating abnormalities in
the sarcomere structure as an alternative method for assessing the risk of drug-induced alterations
of cardiac contractility, because sarcomeres are major components of the myofibrillar fibers and are
responsible for myocardial contraction and relaxation (Sequeira et al., 2014). Morphological
observation by electron microscopy is a useful method to evaluate drug-induced alterations of
sarcomere structure in vitro. However, similar to isolated perfused heart investigations, this
technique is also time-consuming, labor-intensive, and expensive, hindering its routine use.
Alternatively, a high-content imaging system can be used to quantify morphological changes in a highthroughput manner with high reproducibility (Singh et al., 2014). In fact, several in vitro assays to
predict drug-induced toxicities such as liver toxicity and neurotoxicity have demonstrated the value
of this platform for safety assessments in the preclinical stage of drug development by facilitating the
accurate quantification of drug-induced cellular morphological changes (Martin et al., 2014;Sirenko
et al., 2014;Wilson et al., 2014).
In the present study, I developed a simple two-dimensional (2D) morphological assessment system,
2DMA, using human iPSC-CMs with a high-content imaging device to predict drug-induced
cardiotoxicity in humans. ...

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