Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes.
Toxicol Lett
; 285: 74-80, 2018 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-29305325
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptor ErbB-2
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Miocitos Cardíacos
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Células Madre Pluripotentes Inducidas
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Trastuzumab
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Antineoplásicos Inmunológicos
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Modelos Biológicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Toxicol Lett
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos