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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Calcium / metabolism
  • Cardiotoxicity / genetics
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • Disease Susceptibility
  • Doxorubicin / adverse effects
  • Doxorubicin / pharmacology*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Heart Failure / chemically induced*
  • Heart Failure / genetics
  • Humans
  • Induced Pluripotent Stem Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Middle Aged
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Oxidative Stress / drug effects*
  • Polymorphism, Single Nucleotide
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Transcriptome

Substances

  • Antibiotics, Antineoplastic
  • Reactive Oxygen Species
  • Doxorubicin
  • Calcium