Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
Computational Sciences, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
Br J Pharmacol. 2017 Nov;174(21):3766-3779. doi: 10.1111/bph.13713. Epub 2017 Feb 8.
In the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity.
Video microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS-CMs was done at the end of the experiment.
Different cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression.
We have shown that a parallel assessment of motion field imaging-derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS-CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de-risking of compounds at earlier stages of drug discovery.
This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.
在制药行业，对慢性心脏安全风险的评估主要是在临床前药物开发的后期阶段使用体内动物模型进行的。在这里，我们探索了人诱导多能干细胞衍生的心肌细胞（hiPS-CMs）在检测药物诱导的心肌毒性等慢性心脏风险方面的潜力。
基于视频显微镜的运动场成像被应用于评估心脏毒性药物对 hiPS-CMs 收缩运动的慢性影响（超过 72 小时）。同时，从细胞培养基中分析了心肌肌钙蛋白 I（cTnI）、心脏脂肪酸结合蛋白（FABP3）和 N 端脑利钠肽前体（NT-proBNP）的释放情况，并在实验结束时对 hiPS-CMs 的转录谱进行了分析。
不同的心脏毒性药物改变了 hiPS-CMs 的收缩运动特性，同时增加了心脏生物标志物的释放。FABP3 和 cTnI 被证明是预测 hiPS-CMs 心脏毒性的潜在替代物，而 NT-proBNP 似乎是一种价值较低的生物标志物。此外，砷三氧化物、阿霉素或帕比司他慢性暴露于 hiPS-CMs 引起的药物诱导性心脏毒性与收缩参数、生物标志物释放和转录表达的不同变化模式有关。
我们已经表明，对运动场成像衍生的收缩特性、生物标志物释放和转录变化的平行评估可以检测 hiPS-CMs 中慢性药物诱导的心脏毒性的不同机制。因此，hiPS-CMs 有可能在药物发现的早期阶段改善和加速化合物的心血管风险降低。
本文是关于化疗药物引起的心脏毒性的新见解专题部分的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.
