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Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models

Authors
 Jae-Ho Cheong ; Eun Sung Park ; Jiyong Liang ; Jennifer B Dennison ; Dimitra Tsavachidou ; Catherine Nguyen-Charles ; Kwai Wa Cheng ; Hassan Hall ; Dong Zhang ; Yiling Lu ; Murali Ravoori ; Vikas Kundra ; Jaffer Ajani ; Ju-Seog Lee ; Waun Ki Hong ; Gordon B Mills 
Citation
 Molecular Cancer Therapeutics, Vol.10(12) : 2350~2362, 2011 
Journal Title
 Molecular Cancer Therapeutics 
ISSN
 1535-7163 
Issue Date
2011
Abstract
Tumor cell proliferation requires both growth signals and sufficient cellular bioenergetics. The AMP-activated protein kinase (AMPK) pathway seems dominant over the oncogenic signaling pathway suppressing cell proliferation. This study investigated the preclinical efficacy of targeting the tumor bioenergetic pathway using a glycolysis inhibitor 2-deoxyglucose (2DG) and AMPK agonists, AICAR and metformin. We evaluated the in vitro antitumor activity of 2DG, metformin or AICAR alone, and 2DG in combination either with metformin or AICAR. We examined in vivo efficacy using xenograft mouse models. 2DG alone was not sufficient to promote tumor cell death, reflecting the limited efficacy showed in clinical trials. A combined use of 2DG and AICAR also failed to induce cell death. However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy. Gene expression analysis and functional assays revealed that the selective AMPK agonist AICAR augments mitochondrial energy transduction (OXPHOS) whereas metformin compromises OXPHOS. Importantly, forced energy restoration with methyl pyruvate reversed the cell death induced by 2DG and metformin, suggesting a critical role of energetic deprivation in the underlying mechanism of cell death. The combination of 2DG and metformin inhibited tumor growth in mouse xenograft models. Deprivation of tumor bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for a broad spectrum of human tumors
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/95114
DOI
10.1158/1535-7163.MCT-11-0497
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Surgery
1. 연구논문 > 5. Research Institutes > Institute for Medical Convergence
Yonsei Authors
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