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Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.

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Title: Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.
Authors: Chaudhari, U
Nemade, H
Wagh, V
Gaspar, JA
Ellis, JK
Srinivasan, SP
Spitkovski, D
Nguemo, F
Louisse, J
Bremer, S
Hescheler, J
Keun, HC
Hengstler, JG
Sachinidis, A
Item Type: Journal Article
Abstract: The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity.
Issue Date: 4-Nov-2015
Date of Acceptance: 20-Oct-2015
URI: http://hdl.handle.net/10044/1/27641
DOI: https://dx.doi.org/10.1007/s00204-015-1623-5
ISSN: 1432-0738
Publisher: Springer Verlag (Germany)
Start Page: 2763
End Page: 2777
Journal / Book Title: Archives of Toxicology
Volume: 90
Issue: 11
Copyright Statement: © The Author(s) 2015. This article is published with open access at Springerlink.com
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 266838
Keywords: Cardiotoxicity
Genomic biomarkers
Heart failure
Human stem cells derived cardiomyocytes
In vitro test system
Safety assessment
Transcriptomics
Toxicology
1115 Pharmacology And Pharmaceutical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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