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

Paul W. Burridge*, Yong Fuga Li, Elena Matsa, Haodi Wu, Sang Ging Ong, Arun Sharma, Alexandra Holmström, Alex C. Chang, Michael J. Coronado, Antje D. Ebert, Joshua W. Knowles, Melinda L. Telli, Ronald M. Witteles, Helen M. Blau, Daniel Bernstein, Russ B. Altman, Joseph C. Wu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

346 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)547-556
Number of pages10
JournalNature Medicine
Volume22
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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