Abstract
Gliomas are the most common and devastating primary tumors of the central nervous system. Ecto-NTPDases and ecto-5'-nucleotidase/CD73 can control extracellular ATP/adenosine levels, which have been described as proliferation factors. Here, we investigate the influence of indomethacin on the enzyme cascade that catalyses the interconversion of purine nucleotides in U138-MG and C6 glioma cell lines. Exposure of glioma cells to 100 microM indomethacin for 48 h caused increases of 52% (P < 0.05) and 62% (P < 0.05) in the AMP hydrolysis rate in C6 and U138-MG cell lines, respectively. Indomethacin treatments also increased ATP hydrolysis. Significant increase in ecto-5'-nucleotidase/CD73 mRNA and protein levels were observed after treatment with indomethacin. Pretreatment of glioma cells with a specific antagonist of the adenosine A(3) receptor, MRS1220 (1 microM; 9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline), significantly reduced the inhibition of cell proliferation induced by indomethacin. In addition, a significant increase in mRNA levels of the adenosine A(3) receptor was observed after treatment with indomethacin. In conclusion, our data indicate that adenosine A(3) receptors and the enzyme, ecto-5'-nucleotidase/CD73, are involved in the anti-proliferative effect of indomethacin in glioma cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5'-Nucleotidase / genetics*
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5'-Nucleotidase / metabolism
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Actins / metabolism
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Adenosine Diphosphate / analogs & derivatives
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Adenosine Diphosphate / metabolism
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Adenosine Monophosphate / metabolism
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / metabolism
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Adenosine Triphosphate / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dimethyl Sulfoxide / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Flow Cytometry
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Gene Expression Regulation, Enzymologic / drug effects
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Glioma / enzymology
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Glioma / genetics
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Glioma / pathology
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Humans
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Indomethacin / pharmacology*
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Purinergic P1 Receptor Agonists
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Purinergic P1 Receptor Antagonists
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Quinazolines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Theophylline / analogs & derivatives
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Theophylline / pharmacology
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Time Factors
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Triazoles / pharmacology
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Xanthines / pharmacology
Substances
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9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline
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Actins
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Anti-Inflammatory Agents, Non-Steroidal
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Purinergic P1 Receptor Agonists
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Purinergic P1 Receptor Antagonists
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Quinazolines
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RNA, Messenger
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Triazoles
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Xanthines
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8-cyclopentyl-1,3-dimethylxanthine
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Adenosine Monophosphate
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Adenosine Diphosphate
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Adenosine Triphosphate
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1,3-dipropyl-8-cyclopentylxanthine
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Theophylline
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5'-Nucleotidase
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alpha,beta-methyleneadenosine 5'-triphosphate
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Indomethacin
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Dimethyl Sulfoxide