title: Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes.
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.
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.
authors.forename: Agnes
authors.initials: A
authors.lastname: Maillet
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.
authors.forename: Kim
authors.initials: K
authors.lastname: Tan
authors.affiliation: Center for Computational Biology, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Chai
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.
authors.forename: Singh N
authors.initials: SN
authors.lastname: Sadananda
authors.affiliation: National Heart Research Institute, National Heart Centre Singapore, Singapore.|Cardiovascular Academic Clinical Program, DUKE-NUS Graduate Medical School, Singapore.
authors.forename: Ashish
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.
authors.forename: Jolene
authors.initials: J
authors.lastname: Ooi
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.|Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.affiliation: Center for Computational Biology, Duke-NUS Graduate Medical School, Singapore.|Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: National Heart Research Institute, National Heart Centre Singapore, Singapore.|Cardiovascular Academic Clinical Program, DUKE-NUS Graduate Medical School, Singapore.
authors.forename: Winston
authors.initials: W
authors.lastname: Shim
authors.affiliation: Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.|Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors.forename: Liam R
authors.initials: LR
authors.lastname: Brunham
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D066126:Cardiotoxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin