Effects of methotrexate on nucleotide pools in normal human T cells and the CEM T cell line

Budzik, Gerald P.; Colletti, Lynn; Faltynek, Connie R.

doi:10.1016/s0024-3205(00)00559-2

Cited by 35 publications

(24 citation statements)

References 30 publications

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“…38,39 MTX decreased the ATIC transformylase and the total enzyme activity, whereas its cyclohydrolase function remained unaffected ( Figure 7A). In the presence of NPM-ALK, the effect of the MTX was partially abrogated, and higher doses of MTX were required to produce similar inhibitory rates compared with samples lacking NPM-ALK.…”

Section: Npm-alk Protects Cancer Cells From the Effects Of Mtxmentioning

confidence: 98%

The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Boccalatte¹,

Voena²,

Riganti

et al. 2009

Blood

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Section: Npm-alk Protects Cancer Cells From the Effects Of Mtxmentioning

confidence: 98%

The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Boccalatte¹,

Voena²,

Riganti

et al. 2009

Blood

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“…The antiproliferative properties of high-dose MTX are due to inhibition of dihydrofolate reductase and other folate-dependent enzymes, which inhibit both purine and pyrimidine nucleotide biosynthesis (2)(3)(4)(5). At high levels, MTX inhibits cells in the S phase of cell cycle and slows the entry of cells from the G 1 phase into S phase (6,7).…”

Section: Modulation Of Orphan Nuclear Receptor Nurr1 Expression By Mementioning

confidence: 99%

Modulation of Orphan Nuclear Receptor NURR1 Expression by Methotrexate in Human Inflammatory Joint Disease Involves Adenosine A2A Receptor-Mediated Responses

Ralph

McEvoy

Kane

et al. 2005

The Journal of Immunology

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Modulation by proinflammatory mediators indicate that NURR1 induction represents a point of convergence of distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals. The present study identifies NURR1 as a molecular target of methotrexate (MTX) action in human inflammatory joint disease and examines the mechanism through which MTX modulates NURR1 expression. MTX significantly suppresses expression of NURR1 in vivo in patients with active psoriatic arthritis (n = 10; p < 0.002) who were prescribed low-dose MTX for management of peripheral arthritis. Importantly, reduction in NURR1 levels correlate (n = 10; r = 0.57; p = 0.009) with changes in disease activity score (both clinical and laboratory parameters). MTX selectively modulates NURR1 levels induced by inflammatory stimuli and growth factors in resident cell populations of synovial tissue. In primary human synoviocytes and microvascular endothelial cells, we observe dose-dependent differential effects of MTX on steady-state and inducible NURR1 levels. Our data confirms that adenosine, and its stable analog 5′-N-ethylcarboxamideadenosine, can mimic the differential effects of MTX on NURR1 transcription. In addition, we verify that the inhibitory effect of low-dose MTX on NURR1 activation is mediated through the adenosine receptor A2. More specifically, our data distinguishes the selective involvement of the A2A receptor subtype in these responses. In summary, these findings establish the nuclear orphan receptor NURR1 as a molecular target of MTX action in human inflammatory joint disease and demonstrate that the immunomodulatory actions of MTX on NURR1 expression are mediated through adenosine release.

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“…In addition, methotrexate polyglutamate derivatives that accumulate in cells are the direct inhibitors of both ATIC and GART, but they most potently inhibit ATIC (13 -15). The net result is an inhibition of the de novo purine biosynthesis leading to a depletion of ATP and to a lesser extent of GTP (15,16). In contrast to normal cells, which prefer the purine salvage pathway, rapidly dividing tumor cells rely on the de novo pathways explaining part of the chemotherapeutic action of methotrexate.…”

Section: Introductionmentioning

confidence: 99%

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

Beckers

Organe

Timmermans

et al. 2006

Molecular Cancer Therapeutics

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Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA ribosideinduced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention. [Mol Cancer Ther 2006;5(9):2211 -7]

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Effects of methotrexate on nucleotide pools in normal human T cells and the CEM T cell line

Cited by 35 publications

References 30 publications

The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Modulation of Orphan Nuclear Receptor NURR1 Expression by Methotrexate in Human Inflammatory Joint Disease Involves Adenosine A2A Receptor-Mediated Responses

Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside

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