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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
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