title: Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models.
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.
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. jhcheong@yuhs.ac
authors: Jae-Ho
authors: JH
authors: Cheong
authors: Eun Sung
authors: ES
authors: Park
authors: Jiyong
authors: J
authors: Liang
authors: Jennifer B
authors: JB
authors: Dennison
authors: Dimitra
authors: D
authors: Tsavachidou
authors: Catherine
authors: C
authors: Nguyen-Charles
authors: Kwai
authors: K
authors: Wa Cheng
authors: Hassan
authors: H
authors: Hall
authors: Dong
authors: D
authors: Zhang
authors: Yiling
authors: Y
authors: Lu
authors: Murali
authors: M
authors: Ravoori
authors: Vikas
authors: V
authors: Kundra
authors: Jaffer
authors: J
authors: Ajani
authors: Ju-Seog
authors: JS
authors: Lee
authors: Waun
authors: W
authors: Ki Hong
authors: Gordon B
authors: GB
authors: Mills
mesh_terms: D000818:Animals; D003847:Deoxyglucose / Q000008:administration & dosage / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D003847:Deoxyglucose