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The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling

Rationale: Lapatinib (LAP) is a crucial alternative to trastuzumab upon the onset of drug resistance during treatment of metastatic human epidermal growth factor receptor 2-positive breast cancer. Like trastuzumab, LAP is commonly used alongside anthracyclines as a combination therapy, due to enhanc...

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Autores principales: Hsu, Wan-Tseng, Huang, Ching-Ying, Yen, Christopher Y.T., Cheng, Ann-Lii, Hsieh, Patrick C.H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010982/
https://www.ncbi.nlm.nih.gov/pubmed/29930721
http://dx.doi.org/10.7150/thno.23207
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author Hsu, Wan-Tseng
Huang, Ching-Ying
Yen, Christopher Y.T.
Cheng, Ann-Lii
Hsieh, Patrick C.H.
author_facet Hsu, Wan-Tseng
Huang, Ching-Ying
Yen, Christopher Y.T.
Cheng, Ann-Lii
Hsieh, Patrick C.H.
author_sort Hsu, Wan-Tseng
collection PubMed
description Rationale: Lapatinib (LAP) is a crucial alternative to trastuzumab upon the onset of drug resistance during treatment of metastatic human epidermal growth factor receptor 2-positive breast cancer. Like trastuzumab, LAP is commonly used alongside anthracyclines as a combination therapy, due to enhanced anti-cancer efficacy. However, this is notably associated with cardiotoxicity so it is imperative to understand the mechanisms driving this cardiotoxicity and develop cardioprotective strategies. To this end, here we utilize human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), which exhibit several characteristics representative of in vivo cardiomyocytes that make them breakthrough models to study drug toxicity. Methods: We investigated LAP- and doxorubicin (DOX)-induced toxicity in hPSC-CMs and evaluated the involvement of inducible nitric oxide (NO) synthase (iNOS). The significance of iNOS-mediated cardiotoxicity was furthermore evaluated in animal studies. Results: LAP synergistically increased DOX toxicity in hPSC-CMs in a dose- and time-dependent manner. At concentrations that were otherwise non-apoptotic when administered separately, LAP significantly potentiated DOX-induced hPSC-CM apoptosis. This was accompanied by increased iNOS expression and pronounced production of NO. iNOS inhibition significantly reduced hPSC-CM sensitivity to LAP and DOX co-treatment (LAP-plus-DOX), leading to reduced apoptosis. Consistent with our observations in vitro, delivery of an iNOS inhibitor in mice treated with LAP-plus-DOX attenuated myocardial apoptosis and systolic dysfunction. Moreover, inhibition of iNOS did not compromise the anti-cancer potency of LAP-plus-DOX in a murine breast cancer xenograft model. Conclusions: Our findings suggest that iNOS inhibition is a promising cardioprotective strategy to accompany HER2-inhibitor/anthracycline combination therapies. Furthermore, these results support the promise of hPSC-CMs as a platform for investigating cardiotoxicity and developing cardioprotectants as a whole.
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spelling pubmed-60109822018-06-21 The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling Hsu, Wan-Tseng Huang, Ching-Ying Yen, Christopher Y.T. Cheng, Ann-Lii Hsieh, Patrick C.H. Theranostics Research Paper Rationale: Lapatinib (LAP) is a crucial alternative to trastuzumab upon the onset of drug resistance during treatment of metastatic human epidermal growth factor receptor 2-positive breast cancer. Like trastuzumab, LAP is commonly used alongside anthracyclines as a combination therapy, due to enhanced anti-cancer efficacy. However, this is notably associated with cardiotoxicity so it is imperative to understand the mechanisms driving this cardiotoxicity and develop cardioprotective strategies. To this end, here we utilize human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), which exhibit several characteristics representative of in vivo cardiomyocytes that make them breakthrough models to study drug toxicity. Methods: We investigated LAP- and doxorubicin (DOX)-induced toxicity in hPSC-CMs and evaluated the involvement of inducible nitric oxide (NO) synthase (iNOS). The significance of iNOS-mediated cardiotoxicity was furthermore evaluated in animal studies. Results: LAP synergistically increased DOX toxicity in hPSC-CMs in a dose- and time-dependent manner. At concentrations that were otherwise non-apoptotic when administered separately, LAP significantly potentiated DOX-induced hPSC-CM apoptosis. This was accompanied by increased iNOS expression and pronounced production of NO. iNOS inhibition significantly reduced hPSC-CM sensitivity to LAP and DOX co-treatment (LAP-plus-DOX), leading to reduced apoptosis. Consistent with our observations in vitro, delivery of an iNOS inhibitor in mice treated with LAP-plus-DOX attenuated myocardial apoptosis and systolic dysfunction. Moreover, inhibition of iNOS did not compromise the anti-cancer potency of LAP-plus-DOX in a murine breast cancer xenograft model. Conclusions: Our findings suggest that iNOS inhibition is a promising cardioprotective strategy to accompany HER2-inhibitor/anthracycline combination therapies. Furthermore, these results support the promise of hPSC-CMs as a platform for investigating cardiotoxicity and developing cardioprotectants as a whole. Ivyspring International Publisher 2018-05-09 /pmc/articles/PMC6010982/ /pubmed/29930721 http://dx.doi.org/10.7150/thno.23207 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Hsu, Wan-Tseng
Huang, Ching-Ying
Yen, Christopher Y.T.
Cheng, Ann-Lii
Hsieh, Patrick C.H.
The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling
title The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling
title_full The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling
title_fullStr The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling
title_full_unstemmed The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling
title_short The HER2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through iNOS signaling
title_sort her2 inhibitor lapatinib potentiates doxorubicin-induced cardiotoxicity through inos signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010982/
https://www.ncbi.nlm.nih.gov/pubmed/29930721
http://dx.doi.org/10.7150/thno.23207
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