title: Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Burridge
authors.affiliation: Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, California, USA.|Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yong Fuga
authors.identifier: 0000-0003-2116-3223
authors.initials: YF
authors.lastname: Li
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Matsa
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Haodi
authors.initials: H
authors.lastname: Wu
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Sang-Ging
authors.initials: SG
authors.lastname: Ong
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Holmström
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Chang
authors.affiliation: Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coronado
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Antje D
authors.initials: AD
authors.lastname: Ebert
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Telli
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Witteles
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Blau
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D066126:Cardiotoxicity / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004198:Disease Susceptibility; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006333:Heart Failure / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D002118:Calcium