Preclinical Development Dual Inhibition of Tumor Energy Pathway by 2-Deoxyglucose and Metformin Is Effective against a Broad Spectrum of Preclinical Cancer Models

Tumor cell proliferation requires both growth signals and sufficient cellular bioenergetics. The AMPactivatedprotein kinase (AMPK) pathway seemsdominant 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 andmetformin. 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 topromote tumor cell death, reflecting the limited efficacy showed in clinical trials.Acombineduse 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 2DGandmetformin inhibited tumor growth inmouse xenograftmodels.Deprivation of tumor bioenergetics bydual inhibition of energypathwaysmight be an effective novel therapeutic approach for a broad spectrumof human tumors. Mol Cancer Ther; 10(12); 2350–62. 2011 AACR.