THE EFFECTS OF 2‐DEOXY‐d‐GLUCOSE ON METABOLISM OF SLICES OF CEREBRAL CORTEX INCUBATED <i>IN VITRO</i>

Tower, Donald B.

doi:10.1111/j.1471-4159.1958.tb12625.x

Cited by 165 publications

(64 citation statements)

References 40 publications

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“…5) by a rapid trapping of Pi relative to its regeneration from phosphorylated intermediates and its limited transport into the cells. Such a disturbance in the balance of Pi metabolism has been described in a variety of cells upon their utilization of other rapidly phosphorylated sugars or their analogs [2, 50,54,55,58,59].…”

Section: Discussionmentioning

confidence: 99%

2-Deoxy-d-galactose Metabolism in Ascites Hepatoma Cells Results in Phosphate Trapping and Glycolysis Inhibition

Smith

Keppler

1977

Eur J Biochem

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The metabolism of 2-deoxy-~-galactose has been studied in AS-30D rat ascites hepatoma cells in suspension. Using 2-deoxy-~-[l-'~C]galactose and an alkaline ethanol deproteinization procedure, the quantitatively identified metabolites included 2-deoxy-~-galactose l-phosphate comprising 99.3%, and UDP-2-deoxy-~-galactose and UDP-2-deoxy-~-glucose, together amounting to 0.4% of the total metabolites. After incubation for 5 h in the presence of 2-deoxy-~-galactose (1 mmol/l), the content of 2-deoxy-~-galactose l-phosphate reached 35 mmol x (kg cells)-'. The rate of phosphorylation of 2-deoxy-~-galactose was rapid during the first 30 min and decreased to approximately 20% of this rate during the subsequent hours.The rapid trapping of Pi in the form of 2-deoxy-~-galactose l-phosphate resulted in a depression of free intracellular Pi in spite of a concomitant increase in net 32Pi uptake from the medium and a decrease of ATP and other 5'-nucleotides. The rates of glucose utilization and lactate production were depressed by more than SO% in the presence of 2-deoxy-~-galactose (1 mmol/l). Interruption of Pi trapping by removal of 2-deoxy-~-galactose from the medium reversed the depressions of Pi and ATP and resulted in a rapid but incomplete relief of glycolysis inhibition. Crossover analysis of glycolytic intermediates indicated an inhibition at the 6-phosphofructokinase step. The depression of glucose utilization may be mediated by the increased level of glucose 6-phosphate, a potent inhibitor of hexokinase. An additional inhibitory effect of a metabolite of 2-deoxy-~-galactose at the 6-phosphofructokinase step was indicated by crossover analysis after reversal of Pi and ATP depressions in the presence of a high intracellular content of 2-deoxy-~-galactose 1 -phosphate.The quantitative analysis of the metabolites of 2-deoxy-~-galactose demonstrated the predominance of the monophosphate and the negligible formation of UDP derivatives of this sugar analog in AS-30D hepatoma cells. This provides a system for the investigation of a galactose analog as a phosphate-trapping agent in the virtual absence of uridylate trapping.

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Section: Discussionmentioning

confidence: 99%

2-Deoxy-d-galactose Metabolism in Ascites Hepatoma Cells Results in Phosphate Trapping and Glycolysis Inhibition

Smith

Keppler

1977

Eur J Biochem

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“…Above all, 2-deoxy-D-glucose (2-DG) and L-fucose have been studied in numerous works both in vitro and in vivo. 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.…”

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

Tomšík

Stoklasová

Mičuda

et al. 2008

Acta Med. (Hradec Kralove, Czech Repub.)

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IntroductionIn the last decades, the possible effects of unsubstituted deoxyhexoses on tumor cells and their use in cancer treatment have been discussed. Above all, 2-deoxy-D-glucose (2-DG) and L-fucose have been studied in numerous works both in vitro and in vivo. 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. The mechanisms include inhibition of phosphatidylinositol 3-kinase/Akt signaling (35), increased production of reactive oxygen species, interference with MAPK pathways and stabilization of p53 (19). Corresponding to this, 2-DG was found to induce cell death by the activation of apoptosis (1). Regardless of the mechanism which triggers apoptosis by either intrinsic (mitochondrial) or extrinsic (receptor) pathways, the apoptotic cells can be recognized by specific morphological changes: membrane blebbing, condensation, fragmentation of nuclear DNA, cleavage of nuclear proteins (e.g. lamin B) and formation of apoptotic bodies.L-fucose (6-deoxy-L-galactose) is the only endogenous deoxyhexose known in humans. Although a research group reported the effect of intravenously administered L-fucose on the size of a rat solid mammary adenocarcinoma in vivo (25, 41) as well as the efficacy of this deoxysugar in vitro (21,24,28,40), no significant cytostatic potency of single L-fucose in vitro or L-fucose monotherapy has been confirmed in the recent literature. However, it has been noted that L-fucose enhances the cytolytic activity of immune system effector cells and the production of cytokines like interleukin 2 and tumor necrosis factor α (30). It is well documented that altered fucosylation plays an important role in the pathogenesis of malignant tumors (3,11,12). A potential antimetastatic effect of L-fucose and L-fucose containing oligosaccharides was reported as well (26).In nature, there is another deoxyhexose -L-rhamnose (6-deoxy-L-mannose) -similar to deoxyglucose. It is synthesized largely in plants and bacteria but not in animal cells (7). Since L-rhamnose can serve as substrate for L-fucose kinase (8), which catalyzes the first step in the salvage pathway for GDP-fucose biosynthesis (3), a hypothesis can be formulated that L-rhamnose could influence the fucosylation and thereby the behavior of tumor cells. The fact that L-rhamnose can be converted into glycosides in mammalian cells has been indeed evidenced by sporadic discoveries of rhamnosides in mammals (14, 34). Moreover, L-rhamnose, which penetrates by non-mediated diffusion into the cells (4), may be partially metabolized or join some human metabolic pathways (6,13 Summary: The effect of unsubstituted deoxyhexoses, 2-deoxy-D-glucose (2-DG) and L-fucose, on tumor cells has been reported in several...

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“…2DG-6-P is not further metabolized, however, and accumulates intracellularly. High concentrations of 2DG-6-P then inhibit glucose-6-phosphate isomerase, blocking glucose oxidation and stimulating a hypoglycemic-like response (Wick et al 1957;Tower 1958;Horton et al 1973).…”

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confidence: 99%

Effects of Acute Metabolic Stress on Striatal Dopamine Release in Healthy Volunteers

Adler

Elman

Weisenfeld

et al. 2000

Neuropsychopharmacology

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THE EFFECTS OF 2‐DEOXY‐d‐GLUCOSE ON METABOLISM OF SLICES OF CEREBRAL CORTEX INCUBATED IN VITRO

Cited by 165 publications

References 40 publications

2-Deoxy-d-galactose Metabolism in Ascites Hepatoma Cells Results in Phosphate Trapping and Glycolysis Inhibition

2-Deoxy-d-galactose Metabolism in Ascites Hepatoma Cells Results in Phosphate Trapping and Glycolysis Inhibition

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

Effects of Acute Metabolic Stress on Striatal Dopamine Release in Healthy Volunteers

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