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Iran J Med Sci. 2019 Mar;44(2):99-107.

Induction of Apoptosis by a Combination of 2-Deoxyglucose and Metformin in Esophageal Squamous Cell Carcinoma by Targeting Cancer Cell Metabolism.

Author information

1
Department of Radiology-Faculty of Paramedicine- Tabriz University of Medical Sciences, Tabriz, Iran.
2
Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
3
Department of Medical Radiation Science, School of Paramedicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
4
Department of Medical Biotechnology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
5
Department of Radiation Medicine, Faculty of Nuclear Engineering, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
6
Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
7
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
8
Department of Statistics and Epidemiology, Tabriz University of Medical Sciences, Tabriz, Iran.

Abstract

Background:

Both mitochondrial dysfunction and aerobic glycolysis are signs of growing aggressive cancer. If altered metabolism of cancer cell is intended, using the glycolysis inhibitor (2-deoxyglucose (2DG)) would be a viable therapeutic method. The AMP-activated protein kinase (AMPK), as a metabolic sensor, could be activated with metformin and it can also launch a p53-dependent metabolic checkpoint and might inhibit cancer cell growth.

Methods:

After treatment with 5 mM metformin and/or 500 µM 2DG, the TE1, TE8, and TE11 cellular viability and apoptosis were assessed by MTT, TUNEL, and ELISA methods. The changes in p53 and Bcl-2 genes expression levels were examined using real-time PCR method. Data were analyzed by Kruskal-Wallis test using the SPSS 17.0 software.

Results:

Metformin and 2DG, alone and in combination, induced apoptosis in the cell lines. Real-time PCR revealed that metformin induced apoptosis in TE8 and TE11 cells by activating p53, down-regulating Bcl-2 expression. The induced apoptosis by 2DG raised by metformin and the combination modulated the expression of Bcl-2 protein in all cell lines and it was more effective in TE11 cell line.

Conclusion:

Metformin induced apoptosis in ESCC by down-regulating Bcl-2 expression, and up-regulating p53 and induced apoptosis increased by 2-deoxy-d-glucose. Thus, the combination therapy is an effective therapeutic strategy for esophageal squamous cell carcinoma.

KEYWORDS:

Apoptosis; Esophageal carcinoma ; Metformin ; 2-Deoxy-D-Glucose

PMID:
30936596
PMCID:
PMC6423430

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