Bernardi Andressa, Bavaresco Luci, Wink Márcia R, Jacques-Silva Maria C, Delgado-Cañedo Andrés, Lenz Guido, Battastini Ana M O
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Av. Ramiro Barcelos, 2600-anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Eur J Pharmacol. 2007 Aug 13;569(1-2):8-15. doi: 10.1016/j.ejphar.2007.04.058. Epub 2007 May 22.
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.
神经胶质瘤是中枢神经系统最常见且最具破坏性的原发性肿瘤。胞外核苷酸焦磷酸酶和胞外5'-核苷酸酶/CD73可控制细胞外ATP/腺苷水平，而这些物质已被描述为增殖因子。在此，我们研究吲哚美辛对催化U138-MG和C6神经胶质瘤细胞系中嘌呤核苷酸相互转化的酶级联反应的影响。将神经胶质瘤细胞暴露于100微摩尔吲哚美辛中48小时，分别使C6和U138-MG细胞系中的AMP水解速率提高了52%（P < 0.05）和62%（P < 0.05）。吲哚美辛处理还增加了ATP水解。用吲哚美辛处理后，观察到胞外5'-核苷酸酶/CD73的mRNA和蛋白水平显著增加。用腺苷A(3)受体的特异性拮抗剂MRS1220（1微摩尔；9-氯-2-(2-呋喃基)-5-((苯乙酰基)氨基)-[1,2,4]三唑并[1,5-c]喹唑啉）预处理神经胶质瘤细胞，可显著降低吲哚美辛诱导的细胞增殖抑制作用。此外，用吲哚美辛处理后，观察到腺苷A(3)受体的mRNA水平显著增加。总之，我们的数据表明腺苷A(3)受体和胞外5'-核苷酸酶/CD73酶参与了吲哚美辛对神经胶质瘤细胞的抗增殖作用。
