Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes

Yosuke K. Kurokawa, Michael R. Shang, Rose T. Yin, Steven George

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Trastuzumab (Herceptin®), a monoclonal antibody against the ErbB2 (HER2) receptor, has significantly improved clinical outcomes for HER2+ breast cancer patients. However, the drug also has known cardiotoxic side effects through mechanisms that are not fully understood. Here we utilized human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the cardioprotective effects of ErbB2/4 signaling is observed. We observed no cardioprotective effects of ErbB2/4 signaling without cellular stress (doxorubicin exposure in this study). In addition to neuregulin-1 (NRG-1), we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF) also provides cardioprotective effects for iPS-CMs. Finally, we demonstrate a simple, high-throughput co-culture platform utilizing iPS-CMs and endothelial cells that is capable of detecting trastuzumab-related cardiotoxicity. We conclude that iPS-CMs can recapitulate trastuzumab-related cardiotoxicity, and may be used to elucidate additional modes of toxicity of trastuzumab and related compounds.

Original languageEnglish (US)
Pages (from-to)74-80
Number of pages7
JournalToxicology Letters
Volume285
DOIs
StatePublished - Mar 15 2018

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Stem cells
Cardiac Myocytes
Stem Cells
Induced Pluripotent Stem Cells
Neuregulin-1
Cell signaling
Endothelial cells
Coculture Techniques
Cardiotoxicity
In Vitro Techniques
Trastuzumab
Cell culture
Epidermal Growth Factor
Doxorubicin
Toxicity
Heparin
Intercellular Signaling Peptides and Proteins
Endothelial Cells
Monoclonal Antibodies
Throughput

Keywords

  • Cardiotoxicity
  • ErbB2
  • Neuregulin
  • Stem cell-derived cardiomyocytes

ASJC Scopus subject areas

  • Toxicology

Cite this

Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes. / Kurokawa, Yosuke K.; Shang, Michael R.; Yin, Rose T.; George, Steven.

In: Toxicology Letters, Vol. 285, 15.03.2018, p. 74-80.

Research output: Contribution to journalArticle

Kurokawa, Yosuke K. ; Shang, Michael R. ; Yin, Rose T. ; George, Steven. / Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes. In: Toxicology Letters. 2018 ; Vol. 285. pp. 74-80.
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