Metformin inhibits proliferation and cytotoxicity and induces apoptosis via AMPK pathway in CD19-chimeric antigen receptor-modified T cells
Q Mu, M Jiang, Y Zhang, F Wu, H Li… - OncoTargets and …, 2018 - Taylor & Francis
Q Mu, M Jiang, Y Zhang, F Wu, H Li, W Zhang, F Wang, J Liu, L Li, D Wang, W Wang, S Li…
OncoTargets and therapy, 2018•Taylor & FrancisBackground 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 …
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 …
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.
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