Imbalance in Nucleotide Pools of Myeloid Leukemia Cells and HL-60 Cells: Correlation with Cell Cycle Phase, Cell Proliferation and Differentiation

Korte, Dirk de; Haverkort, Willem A.; Boer, Martin de; Roos, Dirk; Gennip, Albert H.

doi:10.1007/978-1-4684-1248-2_68

Cited by 4 publications

(4 citation statements)

References 8 publications

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“…Alterations in ribonucleotide pools have been observed in various malignancies (Jackson et al, 1980;Weber et al, 1983;De Korte et al, 1987;Slingerland et al, 1995) including lymphoblasts of paediatric patients with ALL, with the increase in CTP concentration being most pronounced (De Korte et al, 1986). Our study showed that there seems to be a correlation between the activity of CTP synthetase and the concentration of CTP in the patients' samples.…”

Section: Discussionsupporting

confidence: 61%

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

Verschuur

Gennip²,

Leen³

et al. 2000

Br J Haematol

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Summary. Cytidine triphosphate (CTP) synthetase is a key enzyme for the synthesis of cytosine (deoxy)ribonucleotides, catalysing the conversion of uridine triphosphate (UTP) into CTP, and has a high activity in several malignancies. In this preclinical study, the enzyme activity and mRNA expression of the enzyme and (deoxy)ribonucleotide concentrations were analysed in leukaemic cells of 57 children suffering from acute lymphocytic leukaemia (ALL). In addition, in vitro experiments were performed with the CTP synthetase inhibitor cyclopentenyl cytosine (CPEC). A significantly higher activity of CTP synthetase (6´5^3´9 nmol CTP/ mg/h) was detected in ALL cells than in lymphocytes of healthy controls (1´8^0´9 nmol CTP/mg/h, P , 0´001) that was independent of white blood cell (WBC) count, blast percentage, age, gender or type of ALL. The enzyme activity was not correlated with the CTP synthetase mRNA expression. The activity of CTP synthetase in ALL cells compared with non-malignant CD341 bone marrow controls (5´6^2´4 nmol CTP/mg/h) was not statistically different. In vitro treatment of ALL cells with CPEC induced a dose-dependent decrease of the CTP concentration. The lowest concentration of CPEC (0´63 mm) induced a depletion of CTP of 41^20% and a depletion of dCTP of 27^21%. The degree of CTP depletion of ALL cells after treatment with CPEC was positively correlated with the activity of CTP synthetase. The inhibition of CTP synthetase in situ was confirmed by flux studies using radiolabelled uridine. From these results, it can be expected that CPEC has a cytostatic effect on lymphoblasts of children with ALL.

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Section: Discussionsupporting

confidence: 61%

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

Verschuur

Gennip²,

Leen³

et al. 2000

Br J Haematol

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“…In addition to supplying precursors for the de novo synthesis of nucleotides, glucose and glutamine provide energy by coupling catabolic or oxidative reactions to nucleotide phosphorylation (Henderson and Paterson, 1973). These nucleotide pools are fundamental to cellular metabolism and fluctuations in the nucleotide levels have been shown to lead to changes in cell behavior such as growth rate and differentiation (De Korte et al, 1987;Ryll and Wagner, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Barnabé

Butler

2000

Cytotechnology

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The effects of media concentrations of glucose andglutamine on the intracellular nucleotide pools andoxygen uptake rates of a murine antibody-secretinghybridoma cell line were investigated. Cells takenfrom mid-exponential phase of growth were incubated inmedium containing varying concentrations of glucose(0-25 mM) and glutamine (0-9 mM). The intracellularconcentrations of ATP, GTP, UTP and CTP, and theadenylate energy charge increased concomitantly withthe medium glucose concentration. The total adenylatenucleotide concentration did not change over a glucose concentration range of 1-25 mM but therelative levels of AMP, ADP and ATP changed as theenergy charge increased from 0.36 to 0.96. Themaximum oxygen uptake rate (OUR) was obtained in thepresence of 0.1-1 mM glucose. However at glucoseconcentrations >1 mM the OUR decreased suggestinga lower level of aerobic metabolism as a result of theCrabtree effect.A low concentration of glutamine (0.5 mM) caused asignificant increase (45-128%) in the ATP, GTP,CTP, UTP, UDP-GNac, and NAD pools and a doubling ofthe OUR compared to glutamine-free cultures. Theminimal concentration of glutamine also caused anincrease in the total adenylate pool indicating thatthe amino acid may stimulate thede novosynthesis of nucleotides. However, all nucleotidepools and the OUR remained unchanged within the rangeof 0.5-9 mM glutamine.Glucose was shown to be the major substrate forenergy metabolism. It was estimated that in thepresence of high concentrations of glucose (10-25 mM),glutamine provided the energy for the maintenance ofup to 28% of the intracellular ATP pool, whereas theremainder was provided by glucose metabolism.

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“…Aberrant pyrimidine elevations have been associated with several types of cytoproliferative disease including cancers and autoimmune diseases (Bökkerink, 1986;de Korte, 1987;Huang, 2002;Jackson, 1980;Weber, 1983;Huang, 2004;Löffler 2005;Wahl 1979;Cysyk, 1995;Karle, 1984); uracil has been reported as a potent promoter of urinary bladder carcinogenesis in rats (Shirai, 1986). This and other evidence suggest the possibility of a causative role for elevated pyrimidines in pathological cytoproliferation.…”

Section: Introductionmentioning

confidence: 97%

Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent and Include p53 Repression: DNA-Synthesis-Independent Proliferative Mechanisms of Elevated Pyrimidines

Gipson¹

2014

j pharmaceut sci pharmacol

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Several types of cytoproliferative diseases, including cancers and autoimmune diseases, are associated with elevated cellular levels of pyrimidine nucleotides. This review assembles literature evidence supporting a thesis that elevated pyrimidine levels drive cytoproliferation largely through DNA-synthesis-independent mechanisms, which circumstance, it is proposed, inherently limits clinical efficacy of DNA-synthesis-targeting cytostatic drugs. Five hypothetical mechanisms, with supporting literature evidence, are presented: (1) Pyrimidine nucleotides released from ion channels auto/paracrinally and persistently activate the EGFR, PKC and ERK signaling pathway, upregulating cytokines and Cdk2; (2) One effect of ERK activation is reversal of allosteric control of de novo pyrimidine biosynthesis; thus pyrimidines' auto/paracrine ERK activation may reflect positive autoregulation; (3) Elevated intracellular pyrimidine nucleotides preferentially upregulate tumorigenic genes; (4) Elevated pyrimidines promote aberrant glycosylation of transcription factors; and (5) These diverse pyrimidine effects contribute, by different paths yet collectively, to repression of p53 or of its function. Also reviewed are alternate pyrimidine biosynthesis pathways relevant to disease. Based on these hypotheses, a clinical strategy for cytoproliferative disease is proposed that co-targets three cellular processes seen as "linchpins" of pyrimidines' auto/paracrine effects, including targeting alternate pyrimidine biosynthesis pathways.

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Imbalance in Nucleotide Pools of Myeloid Leukemia Cells and HL-60 Cells: Correlation with Cell Cycle Phase, Cell Proliferation and Differentiation

Cited by 4 publications

References 8 publications

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

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Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent and Include p53 Repression: DNA-Synthesis-Independent Proliferative Mechanisms of Elevated Pyrimidines

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