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Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells
BACKGROUND: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892609/ https://www.ncbi.nlm.nih.gov/pubmed/29662316 http://dx.doi.org/10.2147/OTT.S154853 |
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author | Mu, Qian Jiang, Miao Zhang, Yuzhu Wu, Fei Li, Hui Zhang, Wen Wang, Fang Liu, Jiang Li, Liang Wang, Dongshan Wang, Wenjuan Li, Shiwu Song, Haibo Tang, Dongqi |
author_facet | Mu, Qian Jiang, Miao Zhang, Yuzhu Wu, Fei Li, Hui Zhang, Wen Wang, Fang Liu, Jiang Li, Liang Wang, Dongshan Wang, Wenjuan Li, Shiwu Song, Haibo Tang, Dongqi |
author_sort | Mu, Qian |
collection | PubMed |
description | BACKGROUND: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. PURPOSE: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved. METHODS: CD19-CAR T cells proliferation, apoptosis and cytotoxicity were mainly tested by CCK-8 assay, flow cytometry and ELISA. The detection of mechanism primarily used western blot. Bioluminescence imaging is the main application technology of animal studies. RESULTS: In the current study, it was found that metformin inhibited CD19-CAR T cell proliferation and cytotoxicity and induced apoptosis. Furthermore, our study revealed that metformin activated AMPK and suppressed mTOR and HIF1α expression. By using an AMPK inhibitor, compound C, we demonstrated the crucial roles of AMPK in CD19-CAR T cells when they were treated with metformin. Finally, we verified that metformin suppressed the cytotoxicity of CD19-CAR T cell in vivo. CONCLUSION: Taken together, these results indicated that metformin may play an important role in modulating CD19-CAR T cell biological functions in an AMPK-dependent and mTOR/HIF1α-independent manner. |
format | Online Article Text |
id | pubmed-5892609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58926092018-04-16 Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells Mu, Qian Jiang, Miao Zhang, Yuzhu Wu, Fei Li, Hui Zhang, Wen Wang, Fang Liu, Jiang Li, Liang Wang, Dongshan Wang, Wenjuan Li, Shiwu Song, Haibo Tang, Dongqi Onco Targets Ther Original Research BACKGROUND: CD19-chimericantigen receptor (CAR) modified T cells (CD19-CAR T cells) have been well documented to possess potent anti-tumor properties against CD19-expressingleukemia cells. As a traditional medicine, metformin has been widely used to treat type II diabetes mellitus and more recently has become a candidate for the treatment of cancer. However, no report has revealed the direct effect of metformin on CD19-CAR T cell biological function and its underling mechanisms. PURPOSE: The purpose of this research was to explore the effect of metformin on CD19-CAR T cell biological function and the mechanisms involved. METHODS: CD19-CAR T cells proliferation, apoptosis and cytotoxicity were mainly tested by CCK-8 assay, flow cytometry and ELISA. The detection of mechanism primarily used western blot. Bioluminescence imaging is the main application technology of animal studies. RESULTS: In the current study, it was found that metformin inhibited CD19-CAR T cell proliferation and cytotoxicity and induced apoptosis. Furthermore, our study revealed that metformin activated AMPK and suppressed mTOR and HIF1α expression. By using an AMPK inhibitor, compound C, we demonstrated the crucial roles of AMPK in CD19-CAR T cells when they were treated with metformin. Finally, we verified that metformin suppressed the cytotoxicity of CD19-CAR T cell in vivo. CONCLUSION: Taken together, these results indicated that metformin may play an important role in modulating CD19-CAR T cell biological functions in an AMPK-dependent and mTOR/HIF1α-independent manner. Dove Medical Press 2018-04-03 /pmc/articles/PMC5892609/ /pubmed/29662316 http://dx.doi.org/10.2147/OTT.S154853 Text en © 2018 Mu et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Mu, Qian Jiang, Miao Zhang, Yuzhu Wu, Fei Li, Hui Zhang, Wen Wang, Fang Liu, Jiang Li, Liang Wang, Dongshan Wang, Wenjuan Li, Shiwu Song, Haibo Tang, Dongqi Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells |
title | Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells |
title_full | Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells |
title_fullStr | Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells |
title_full_unstemmed | Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells |
title_short | Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells |
title_sort | metformin inhibits proliferation and cytotoxicity and induces apoptosis via ampk pathway in cd19-chimeric antigen receptor-modified t cells |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892609/ https://www.ncbi.nlm.nih.gov/pubmed/29662316 http://dx.doi.org/10.2147/OTT.S154853 |
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