Abstract
Drug-induced off-target cardiotoxicity, particularly following anti-cancer therapy, is a major concern in new drug discovery and development. To ensure patient safety and efficient pharmaceutical drug development, there is an urgent need to develop more predictive cell model systems and distinct toxicity signatures. In this study, we applied our previously proposed repeated exposure toxicity methodology and performed 1H NMR spectroscopy-based extracellular metabolic profiling in culture medium of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to doxorubicin (DOX), an anti-cancer agent. Single exposure to DOX did not show alteration in the basal level of extracellular metabolites while repeated exposure to DOX caused reduction in the utilization of pyruvate and acetate, and accumulation of formate compared to control culture medium. During drug washout, only pyruvate showed reversible effect and restored its utilization by hiPSC-CMs. On the other hand, formate and acetate showed irreversible effect in response to DOX exposure. DOX repeated exposure increased release of lactate dehydrogenase (LDH) in culture medium suggesting cytotoxicity events, while declined ATP levels in hiPSC-CMs. Our data suggests DOX perturbed mitochondrial metabolism in hiPSC-CMs. Pyruvate, acetate and formate can be used as metabolite signatures of DOX induced cardiotoxicity. Moreover, the hiPSC-CMs model system coupled with metabolomics technology offers a novel and powerful approach to strengthen cardiac safety assessment during new drug discovery and development.
Highlights
Drug-induced cardiotoxicity is a leading cause of drug attrition in drug discovery and development
Our study demonstrates that metabolic profiling of media from hiPSC-CM cultures in the presence of cardiotoxicants can provide a unique platform to predict the cardiotoxic potential of pharmaceutical drug candidates
We used our previously established in vitro repeated exposure toxicity methodology (Fig. 1) (Chaudhari et al 2016). 1H Nuclear Magnetic Resonance (NMR) spectroscopy was applied in metabolic profiling of culture medium of hiPSC-CMs model
Summary
Drug-induced cardiotoxicity is a leading cause of drug attrition in drug discovery and development. Till the experimental in vitro and in vivo animal models cannot truly predict cardiotoxicity in humans because of physiological differences between different species. NMR-based metabolite profiling has been used to detect drug responsive to early changes in metabolite levels contributing to the subsequent toxicity (Andreadou et al 2009; Park et al 2009; Zhang et al 2015). Such toxicity-responsive metabolite signatures can be used to predict adverse effect of drug candidates at an early stage of preclinical drug development (Clarke and Haselden 2008; Robertson et al 2011; Wishart 2008)
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