Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
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
_version_ 1783313191037566976
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
work_keys_str_mv AT muqian metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT jiangmiao metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT zhangyuzhu metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT wufei metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT lihui metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT zhangwen metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT wangfang metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT liujiang metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT liliang metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT wangdongshan metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT wangwenjuan metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT lishiwu metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT songhaibo metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells
AT tangdongqi metformininhibitsproliferationandcytotoxicityandinducesapoptosisviaampkpathwayincd19chimericantigenreceptormodifiedtcells