2-Deoxyglucose as an Energy Restriction Mimetic Agent: Effects on Mammary Carcinogenesis and on Mammary Tumor Cell Growth In vitro

Abstract

Dietary energy restriction (DER) is a potent inhibitor of carcinogenesis, but chronic DER in human populations is difficult to sustain. Consequently, interest exists in identifying energy restriction mimetic agents (ERMAs), agents that provide the health benefits of DER without reducing caloric intake. The selection of a candidate ERMAs for this study was based on evidence that DER inhibits carcinogenesis by limiting glucose availability. The study objective was to determine if 2-deoxyglucose (2-DG), a glucose analogue that blocks its metabolism, would inhibit mammary carcinogenesis. Pilot studies were done to establish a dietary concentration of 2-DG that would not affect growth. For the carcinogenesis study, ninety 21-day-old female Sprague-Dawley rats were injected i.p. with 50 mg of 1-methyl-1-nitrosourea per kilogram of body weight. Following injection, animals were ad libitum fed AIN-93G diet containing 0.00%, 0.02%, or 0.03% (w/w) 2-DG for 5 weeks. 2-DG decreased the incidence and multiplicity of mammary carcinomas and prolonged cancer latency (P < 0.05). The 0.02% dose of 2-DG had no effect on circulating levels of glucose, insulin, insulin-like growth factor-I, IGF binding protein-3, leptin, or body weight gain. Using MCF-7 human breast cancer cells to investigate the signaling pathways perturbed by disruption of glucose metabolism, 2-DG reduced cell growth and intracellular ATP in a dose-and timedependent manner (P < 0.01). Treatment with 2-DG increased levels of phosphorylated AMP-activated protein kinase and Sirt-1 and reduced phosphorylated Akt (P < 0.05). These studies support the hypothesis that DER inhibits carcinogenesis, in part, by limiting glucose availability and that energy metabolism is a target for the development of ERMA for chemoprevention. (Cancer Res 2005; 65(15): 7023-30)

Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

“…Because cancer cells are more dependent on glycolysis (Warburg effect), 25 there have been various attempts to block glycolysis as a strategy for inhibiting cancer cells. 8,26 A number of drugs that target mitochondrial oxidative phosphorylation in the tricarboxylic acid cycle, such as AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), oxaloacetate, oligomycin, and metformin, have also been extensively tested. 27,28 In our study, rather than using specific GBM cell lines, we chose GBM-TS, as we believe new therapeutic approaches should target the subpopulation of GBM cells responsible for treatment failure.…”

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

“…In fact, a number of studies have demonstrated that 2DG treatment in rodents produces a number of effects that parallel those of CR, such as reductions in body temperature, heart rate, and circulating glucose and insulin (5,(15)(16)(17) and increases in circulating glucocorticoids and heat-shock proteins (16)(17)(18). Beyond these effects, 2DG has also been shown to confer functional benefits associated with CR, including inhibition of tumor growth (19,20) and increased stress resistance to neurotoxins and cold shock (17,(21)(22)(23).…”

Evaluation of the Antineoplastic Activity of L-rhamnose in vitro. A Comparison with 2-deoxyglucose

“…2-Deoxyglucose is a synthetic glucose analogue that inhibits phospho-hexose isomerase in the initial stage of glycolysis (29,33) and induces glucoseregulated stress affecting tumor cells in particular (9,42). The inhibitory effect of 2-DG on tumor growth has been reported in both in vitro (43) and in vivo (5,10) studies. Glycolysis inhibition and resulting energy depletion trigger apoptotic cell death.…”