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Title: Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes
Authors: Maillet, A 
Tan, K
Chai, X 
Sadananda, S.N
Mehta, A 
Ooi, J
Hayden, M.R 
Pouladi, M.A 
Ghosh, S 
Shim, W 
Brunham, L.R 
Keywords: antineoplastic antibiotic
biological model
cardiac muscle cell
cell culture
cell survival
drug effects
gene expression profiling
pluripotent stem cell
Antibiotics, Antineoplastic
Cell Survival
Cells, Cultured
Electrophysiological Phenomena
Gene Expression Profiling
Models, Biological
Myocytes, Cardiac
Pluripotent Stem Cells
Issue Date: 2016
Citation: Maillet, A, Tan, K, Chai, X, Sadananda, S.N, Mehta, A, Ooi, J, Hayden, M.R, Pouladi, M.A, Ghosh, S, Shim, W, Brunham, L.R (2016). Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes. Scientific Reports 6 : 25333. ScholarBank@NUS Repository.
Abstract: Doxorubicin is a highly efficacious anti-cancer drug but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity (DIC) remain incompletely understood. We investigated the characteristics and molecular mechanisms of DIC in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). We found that doxorubicin causes dose-dependent increases in apoptotic and necrotic cell death, reactive oxygen species production, mitochondrial dysfunction and increased intracellular calcium concentration. We characterized genome-wide changes in gene expression caused by doxorubicin using RNA-seq, as well as electrophysiological abnormalities caused by doxorubicin with multi-electrode array technology. Finally, we show that CRISPR-Cas9-mediated disruption of TOP2B, a gene implicated in DIC in mouse studies, significantly reduces the sensitivity of hPSC-CMs to doxorubicin-induced double stranded DNA breaks and cell death. These data establish a human cellular model of DIC that recapitulates many of the cardinal features of this adverse drug reaction and could enable screening for protective agents against DIC as well as assessment of genetic variants involved in doxorubicin response. © 2016 Nature Publishing Group. All rights reserved.
Source Title: Scientific Reports
ISSN: 20452322
DOI: 10.1038/srep25333
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