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Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells

Authors Mu Q, Jiang M, Zhang Y, Wu F, Li H, Zhang W, Wang F, Liu J, Li L, Wang D, Wang W, Li S, Song H, Tang D

Received 23 October 2017

Accepted for publication 4 January 2018

Published 3 April 2018 Volume 2018:11 Pages 1767—1776

DOI https://doi.org/10.2147/OTT.S154853

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz


Qian Mu,1,2,* Miao Jiang,1,* Yuzhu Zhang,1 Fei Wu,1 Hui Li,1 Wen Zhang,1 Fang Wang,1 Jiang Liu,1 Liang Li,1 Dongshan Wang,3 Wenjuan Wang,1 Shiwu Li,1 Haibo Song,4 Dongqi Tang1

1Gene and Immunotherapy Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Health Management Center, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 4Central Research Laboratory, Zibo Maternal and Child Health Hospital, Affiliated to Shandong Academy of Medical Science, Zibo, People’s Republic of China

*These authors contributed equally to this work

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.

Keywords:
Chimeric antigen receptor, metformin, proliferation, apoptosis, cytotoxicity, AMPK

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