Imperial College London
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ProfessorHectorKeun

Faculty of Medicine, Department of Surgery & Cancer

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 3161h.keun

 
 
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Location

 

officesInstitute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Chaudhari:2015:10.1007/s00204-015-1623-5,
author = {Chaudhari, U and Nemade, H and Wagh, V and Gaspar, JA and Ellis, JK and Srinivasan, SP and Spitkovski, D and Nguemo, F and Louisse, J and Bremer, S and Hescheler, J and Keun, HC and Hengstler, JG and Sachinidis, A},
doi = {10.1007/s00204-015-1623-5},
journal = {Archives of Toxicology},
pages = {2763--2777},
title = {Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.},
url = {http://dx.doi.org/10.1007/s00204-015-1623-5},
volume = {90},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 safet
AU  - Chaudhari,U
AU  - Nemade,H
AU  - Wagh,V
AU  - Gaspar,JA
AU  - Ellis,JK
AU  - Srinivasan,SP
AU  - Spitkovski,D
AU  - Nguemo,F
AU  - Louisse,J
AU  - Bremer,S
AU  - Hescheler,J
AU  - Keun,HC
AU  - Hengstler,JG
AU  - Sachinidis,A
DO  - 10.1007/s00204-015-1623-5
EP  - 2777
PY  - 2015///
SN  - 1432-0738
SP  - 2763
TI  - Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.
T2  - Archives of Toxicology
UR  - http://dx.doi.org/10.1007/s00204-015-1623-5
UR  - http://hdl.handle.net/10044/1/27641
VL  - 90
ER  -
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