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Nat Med. 2016 May;22(5):547-56. doi: 10.1038/nm.4087. Epub 2016 Apr 18.

Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity.

Burridge PW1,2,3,4,5, Li YF6,7, Matsa E1,2,3, Wu H1,2,3, Ong SG1,2,3, Sharma A1,2,3, Holmström A1,2,3, Chang AC1,2,8, Coronado MJ9, Ebert AD1,2,3, Knowles JW1,3, Telli ML10, Witteles RM1,3, Blau HM1,2,8, Bernstein D1,9, Altman RB7,11, Wu JC1,2,3.

Author information

1
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
3
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
4
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
5
Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
6
Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, California, USA.
7
Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA.
8
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
9
Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, Stanford, California, USA.
10
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
11
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

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.

PMID:
27089514
PMCID:
PMC5086256
DOI:
10.1038/nm.4087
[Indexed for MEDLINE]
Free PMC Article

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