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

Smith, David F.; Keppler, Dietrich

doi:10.1111/j.1432-1033.1977.tb11293.x

Cited by 37 publications

(13 citation statements)

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“…The converse may also be true. The conversion of large amounts of galactose may deplete the pool of nucleotides needed for DNA synthesis as indicated by the results of Smith and Keppler (1977) described above, in which they showed that 2-DG is phosphorylated by ascites cells.…”

Section: The Coordinate and Reciprocal Effects Of The Inhibitorsmentioning

confidence: 90%

“…Rat ascites tumor cells fed 2-DG accumulate 2-deoxy-D-galactose-1-phosphate, and this in turn severely depresses glycolysis, probably by inhibition of the 6-phosphofruetokinase (Smith and Keppler, 1977). Another effect of 2-DG on the ascites cells was found to be a depression of the ATP and Pi pools, as well as those of adenine, uracil, and guanine 5' nucleotides (Smith and Keppler, 1977). A similar depression of the ATP and Pi pools was noted in the livers of whole rats receiving 2-DG intraperitoneally (Starling and Keppler, 1977).…”

Section: Effects Of Inhibitors On Metabolismmentioning

confidence: 99%

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A coordinate relationship between theGALK and theTK1 genes of the Chinese hamster

1985

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Chinese hamster cells in culture were treated with various concentrations of thymidine, 5-bromodeoxyuridine, trifluorothymidine, and 2-deoxy-D-galactose. Selection was made for deficiencies in the activities of galactokinase and thymidine kinase. Selection in the presence of thymidine, 5-bromodeoxyuridine, and trifluorothymidine was expected to produce clones deficient in thymidine kinase only, whereas those deficient in galactokinase were expected to be selected in the presence of 2-deoxy-D-galactose. However, it was found that clones growing in the presence of these inhibitors were frequently deficient in both enzymes. Or if a clone was deficient in only one, the deficiency frequently was not expected according to the selection procedure. This indicates some sort of coordinate relationship between the two gene loci, GALK and TK1, which specify galactokinase and thymidine kinase, respectively. GALK and TK1 are linked in all primates and rodents in which linkage determinations have been made. It is therefore probable that this linkage has been conserved for a long period of time. It is suggested that the apparent relationship between the two genes shown by the data presented here, as well as by others, supports the conclusion that linkage has been conserved by natural selection and is therefore not fortuitous.

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Section: The Coordinate and Reciprocal Effects Of The Inhibitorsmentioning

confidence: 90%

Section: Effects Of Inhibitors On Metabolismmentioning

confidence: 99%

A coordinate relationship between theGALK and theTK1 genes of the Chinese hamster

1985

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“…This is a side effect that can be observed with most C-2-modified hexose analogs including 2-deoxy-~-glucosc [8], 2-deoxy-~-galactose [42] and galactosamine [21,43]. Accumulation of the respective sugar analog monophosphate [8,9,33,35,42,44,45] leads to a lowcring of intracellular Pi [8,[42][43][44] that triggers adenine nucleotide catabolism as well as increased Pi uptake into cells, and contributes to the inhibition of glycolysis [8,42,461. Such a decrease in cellular Pi that is due to a diversion of Pi into sugar phosphate and associated with an enhanced Pi uptake from the medium was originally recognized in yeast upon glucose addition [47].…”

Section: Discussionmentioning

confidence: 99%

Uridylate Trapping Induced by the C‐2‐Modified d‐Glucose Analogs Glucosone, Fluoroglucose, and Glucosamine

Holstege

Schulz-Holstege

Henninger

et al. 1982

European Journal of Biochemistry

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The interference of nucleotide metabolism induced by ~-arabino-hexos-2-u~ose (glucosone), 2-deoxy-2-fluoro-D-glucose (fluoroglucose) and, for comparison, 2-amino-2-deoxy-~-glucose (glucosamine) was studied in suspension cultures of TA3 mammary tumor cells. High-performance liquid chromatography, [I4C]uridine labeling and enzymatic analyses revealed that glucosone is metabolized to the U D P derivative leading to a diversion of [I4C]uridylate from UTP into UDP-glucosone. The accumulation of UDP-glucosone, that was measured in TA3 as well as AS-30D hepatoma cells, was associated with a depletion of UTP pools to less than 15'%; of control and a reduction of CTP contents to one third. UTP and CTP deficiency could be rapidly rcversed by addition of uridine to the cell suspension.Fluoroglucose acted both as a uridylate-trapping and as a guanylate-trapping hexose analog lowering the cellular contcnts of UTP and GTP to 5 % and 27 of control, respectively. The lowering of GTP was accompanied by an increase in total acid-soluble guanine nucleotides and a diversion of 84% of the [14C]guanylate into GDP-fluoroglucose. As compared to fluoroglucose and glucosone, glucosamine was less effective in TA3 cells in decreasing the content of UTP. The uridylate-trapping effect of glucosamine was in part compensated by the most active expansion of the acid-soluble uridylate pool; this reflects an enhanced rate of dc m v o pyrimidine synthesis that could be suppressed by the inhibitor 6-azauridine.As a side effect probably resulting from phosphate trapping, glucosone, fluoroglucose, and glucosamine depressed the levels of ATP and of total adenine 5'-nucleotides to a similar though moderate extent.The depletion of UTP, induced by these C-2-modified D-glucose analogs, and additionally of GTP in the case of fluoroglucose, represent a metabolic lesion that may explain their growth inhibitory and cytotoxic effects.Several C-2-modified D-glucose analogs are phosphorylated by hexokinase [l-31; some of them are metabolized further to U D P and/or GDP derivatives [4-61. Tntracellular formation and accumulation of the respective sugar 6-phosphate can result in a fall of inorganic phosphate triggering adenine nucleotide catabolism as one of its consequences [7 -91. Diversion of uridylate for the synthesis of UDP-sugar analogs leads to a lowering of cellular UTP levels and to a consecutive enhancement of the rate of de novo pyrimidine synthesis [lo]. The UTP depletion is followed by an inhibition of RNA synthesis [I I], while some of the C-2-modified UDPDedicated to Professor H. Holzer on the occasion of his 60th birthday. Abhreviutions. Glucosone, ~-arahino-hexos-2-ulose ; FGlc, fluoroglucose, 2-deoxy-2-fluoro-~-g~ucose; GlcN, glucosamine, 2-amino-2-deoxy-D-glucose; 6-AzaUrd, 6-azauridine; CAMP, CGMP, CUMP, sum of total acid-soluble adenine, guanine, and uracil 5'-nucleotides, respectively ; GDPMan, GDP-mannose; UDPGlc, UDP-glucose; UDPHexNAc, UDP-N-acetylhexosamines.Enzymes. Alkalinc phosphatase (EC 3.1.3.1): glucose-6-phosphate deliydrogenase (...

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“…Thus, while 2-DGal will inhibit glycolysis in tumors it will also have the added function of inhibiting protein glycosylation. And, phosphorylation of 2-DGal will deprive the tumor cell of part of its phosphate pool as well [25, 26]. …”

Section: Tumor Glycolysis As a Therapeutic Strategymentioning

confidence: 99%

Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux

Mathupala¹

2011

PRA

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Metabolism in tumors deviates significantly from that of normal tissues. Increasingly, the underlying aberrant metabolic pathways are being considered as novel targets for cancer therapy. Denoted “metabolic targeting”, small molecule drugs are under investigation for focused inhibition of key metabolic steps that are utilized by tumors, since such inhibitors should harbor minimal toxicity towards surrounding normal tissues.This review will examine the primary biochemical pathways that tumors harness to enhance their bioenergetic capacity, which in turn, help their rapid proliferation and metastasis within the host. It is hoped that “metabolite-mimetic” drugs can be utilized to interfere with metabolic flux pathways active within the tumor, and across tumor-microenvironment boundary. In fact, the major pathways of mammalian metabolism, i.e., the carbohydrate, amino-acid, and fatty-acid metabolic pathways have been examined as putative targets for drug development, with some drug candidates advancing to phase II/III stages. In this regard, glucose metabolism, i.e., the glycolytic pathway - that predominates the bio-energetic flux in tumors, and the associated mitochondrial metabolism have received the most attention as suitable “druggable” targets, focused either at the pathway enzymes or at the plasma-membrane-bound metabolite transporters. Outlined in this review are pre-clinical studies that have led to the discovery of promising drug candidates to target tumor-metabolic flux, and ensuing patents, with descriptions of the biochemical rationale for the combinatorial strategy of a particular metabolic pathway-drug candidate pair.

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

Cited by 37 publications

References 47 publications

A coordinate relationship between theGALK and theTK1 genes of the Chinese hamster

A coordinate relationship between theGALK and theTK1 genes of the Chinese hamster

Uridylate Trapping Induced by the C‐2‐Modified d‐Glucose Analogs Glucosone, Fluoroglucose, and Glucosamine

Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux

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