Regulation of the pentose phosphate pathway in human astrocytes and gliomas

Loreck, David; Galarraga, Juan; Feen, J Van der; Phang, James M.; Smith, Barry H.; Cummins, C. J.

doi:10.1007/bf00999507

Cited by 31 publications

(71 citation statements)

References 46 publications

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“…Furthermore, in tissue culture, glioma demonstrates phenotypic changes in the regulatory enzymes of glycolysis, specifically hexokinase and phosphofructokinase, which are consistent with the observed increase in glycolytic rate [21]. In addition, the pentose phosphate pathway in cultured human derived glioma is increased approximately 400% compared to normal astrocytes [22]. An altered form of glucose-6-phosphate dehydrogenase in these malignant cells is not inhibited by ratios of NADPH/NADP + of up to 20 : 1, unlike the enzyme in normal astrocytes, which is inhibited by ratios of 7:1 [22].…”

Section: Discussionsupporting

confidence: 63%

“…Gliomas, like other malignant neoplasms, possess an accelerated intermediary metabolism as an expression of their transformed state [19][20][21][22]. The rCMRGlu of gliomas, as measured by PET-FDG, and the rate of glucose consumption by cultured cells derived from those tumors are closely correlated [2,28].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the pentose phosphate pathway in cultured human derived glioma is increased approximately 400% compared to normal astrocytes [22]. An altered form of glucose-6-phosphate dehydrogenase in these malignant cells is not inhibited by ratios of NADPH/NADP + of up to 20 : 1, unlike the enzyme in normal astrocytes, which is inhibited by ratios of 7:1 [22]. These enzymatic alterations are presumed to fuel the uncontrolled division of neoplastic cells [19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

“…One explanation for this phenomenon is that increased glucose uptake is the expression of an augmented energy metabolism of the tumor, with which it fuels its repair of damage caused by cytotoxic therapy [11, 16--21]. Additionally, an accelerated shunting of glucose may take place through the phosphogluconate pathway [11,22], thus increasing levels of NADPH and providing ribose phosphates for salvage nucleoside synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, the increased rCMRGlu might represent acceleration of aereobic glycolysis and cellular respiration in order to raise the levels of nucleoside triphosphates (NTP) within the tumor and thus increase its bioenergetic state [16][17][18]. Accelerated shunting of glucose through the phosphogluconate pathway could also increase the levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the neoplasm to maintain an adequate oxidation-reduction balance and scavenge free radicals produced by the cytotoxic drugs [11,[19][20][21][22]. Salvage pathways for nucleoside synthesis could also be activated through the phosphogluconate shunt [19,20].…”

Section: Introductionmentioning

confidence: 99%

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Changes in glucose uptake by malignant gliomas: preliminary study of prognostic significance

1991

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Sequential positron emission tomographic scans with [18F]-2-fluorodeoxyglucose (PET-FDG) were performed on 14 patients with malignant gliomas. All patients had prior brain irradiation. Five patients received adjuvant eight-drugs-in-one-day chemotherapy (experimental subjects) and 9 did not (control subjects). Ratios between the maximal tumor regional cerebral metabolic rate for glucose (rCMRGlu) and the contralateral white matter rCMRGlu, the glucose uptake ratio, were determined. Percent changes in the ratio 1 day after chemotherapy in experimental subjects, and 30 days after the baseline scan in controls, were of prognostic significance. In both groups, patients with the largest percent changes in rCMRGlu had the shortest survival. In contrast, the baseline glucose uptake ratio did not predict length of survival.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Changes in glucose uptake by malignant gliomas: preliminary study of prognostic significance

1991

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Metabolic flux analysis of hybridoma cells in different culture media using mass balances

Bonarius

Hatzimanikatis

Meesters

et al. 1996

Biotechnol. Bioeng.

241

174

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The estimation of the intracellular fluxes of mammalian cells using only the mass balances of the relevant metabolites is not possible because the set of linear equations defined by these mass balances is underdetermined. Either additional experimental flux data or additional theoretical constraints are required to find one unique flux distribution out of the solution space that is bound by the mass balances. Here, a method is developed using the latter approach. The uptake and production rates of amino acids, glucose, lactate, O2, CO2, NH4, MAB, and the intracellular amino acid pools have been determined for two different steady‐states. The cellular composition {total protein and protein composition, total lipids and fatty acid distribution, total carbohydrates, DNA and RNA} has been measured to calculate the requirements for biosynthesis. It is shown to be essential to determine the uptake/production rates of ammonia and either carbon dioxide or oxygen. In mammalian cells these are cometabolites of cyclic metabolic pathways. The flux distribution that is found using the Euclidean minimum norm as the additional theoretical constraint and taking either the CO2 or the NAD(P)H mass balance into account is shown to be in agreement with the measured O2 and CO2 metabolic rates. The metabolic fluxes in hybridoma cells in continuous culture at a specific growth rate of 0.83 day−1 are estimated for a medium with (optimal medium) and without (suboptimal medium) Primatone RL, an enzymatic hydrolysate of animal tissue that causes a more than twofold increase in cell density. It is concluded that The majority of the consumed glucose (>90%) is channeled through the pentose‐phosphate pathway in rapidly proliferating cells. Pyruvate oxidation and tricarboxylic acid (TCA) cycle activity are relatively low, i.e., 8% of the glucose uptake in suboptimal and 14% in optimal medium, respectively. Under both conditions, only a small fraction of pyruvate is further oxidized to CO2. The flux from glutamate to α‐ketoglutarate (catalyzed by glutamate dehydrogenase) is almost zero in medium with and even slightly reversed in medium without Primatone RL. Almost all glutamate enters the TCA cycle due to the action of transaminases. Transhydrogenation plays a significant role in hybridoma cells under our experimental conditions. NADPH is produced at relatively high rates (11 × 10−12 to 13 × 10−12 mol · cell−1 · day−1) compared to other fluxes in both culture media. © 1996 John Wiley & Sons, Inc.

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Examination of primary metabolic pathways in a murine hybridoma with carbon‐13 nuclear magnetic resonance spectroscopy

Mancuso

Sharfstein

Tucker

et al. 1994

Biotech & Bioengineering

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Primary metabolism of a murine hybridoma was probed with (13)C nuclear magnetic resonance (NMR) spectroscopy. Cells cultured in a hollow fiber bioreactor were serially infused with [1-(13)C] glucose, [2-(13)C] glucose, and [3-(13)C] glutamine. In vivo spectroscopy of the culture was used in conjunction with off-line spectroscopy of the medium to determine the intracellular concentration of several metabolic intermediates and to determine fluxes for primary metabolic pathways. Intracellular concentrations of pyruvate and alanine were very high relative to levels observed in normal quiescent mammalian cells. Estimates made from labeling patterns in lactate indicate that 76% of pyruvate is derived directly from glycolysis; some is also derived from the malate shunt, the pyruvate/melate shuttle associated with lipid synthesis and the pentose phosphate pathway. The rate of formation of pyruvate from the pentose phosphate pathway was estimated to be 4% of that from glycolysis; This value is a lower limit and the actual value may be higher. Incorporation of pyruvate into the tricarboxylic acid (TCA) cycle appears to occur through only pyruvate dehydrogenase; no pyruvate carboxylase activity was detected. The malate shunt rate was approximately equal to the rate of glutamine uptake. The rate of incorporation of glucosederived acetyl-CoA into lipids was 4% of the glucose uptake rate. The TCA cycle rate between isocitrate and alpha-ketoglutarate was 110% of the glutamine uptake rate.

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Regulation of the pentose phosphate pathway in human astrocytes and gliomas

Cited by 31 publications

References 46 publications

Changes in glucose uptake by malignant gliomas: preliminary study of prognostic significance

Changes in glucose uptake by malignant gliomas: preliminary study of prognostic significance

Metabolic flux analysis of hybridoma cells in different culture media using mass balances

Examination of primary metabolic pathways in a murine hybridoma with carbon‐13 nuclear magnetic resonance spectroscopy

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