Bernardi Andressa, Jacques-Silva Maria C, Delgado-Cañedo Andrés, Lenz Guido, Battastini Ana M O
Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Eur J Pharmacol. 2006 Feb 27;532(3):214-22. doi: 10.1016/j.ejphar.2006.01.008. Epub 2006 Feb 17.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect in a variety of tumors. Several studies have demonstrated unequivocally that certain NSAIDs cause antiproliferative effects independent of cyclooxygenase (COX) activity. In this study, we investigated the effect of chemically unrelated NSAIDs in the proliferation of glioma cell lines and the possible mechanisms involved in indomethacin-mediated inhibition of proliferation in glioma cells lines. The glioma cell lines were treated with NSAIDs and proliferation was measured by cell counting. Indomethacin, acetaminophen, sulindac sulfide and NS-398 (N-[2-cyclohexyloxy)-4-nitrophenyl]methane-sulfonamide) induced a time- and concentration-dependent inhibition of C6 rat glioma cell proliferation. The inhibition of COX by chemically unrelated NSAIDs leads to inhibition of rat and human glioma cell proliferation. The tetrazolium reduction assay (MTT) indicated a reduction in cell viability induced by indomethacin. None of the NSAIDs tested induced caspase-3/7 activation, assayed with a fluorigenic substrate. The indomethacin-induced inhibition of C6 cells proliferation was abrogated by the use of the c-Src inhibitor, PP2 and the MEK inhibitor, PD 098059, suggesting COX-independent mechanisms. Indomethacin decreased the percentage of cells in the S phase, with relative increases in the G0/G1 and/or the G2/M phase. NSAIDs may be clinically important for pharmacological intervention in gliomas.
非甾体抗炎药（NSAIDs）是广泛用于治疗炎症性疾病的药物，并且在多种肿瘤中具有化学预防作用。多项研究已明确表明，某些NSAIDs可产生独立于环氧化酶（COX）活性的抗增殖作用。在本研究中，我们调查了化学结构不相关的NSAIDs对胶质瘤细胞系增殖的影响，以及吲哚美辛介导的胶质瘤细胞系增殖抑制所涉及的可能机制。用NSAIDs处理胶质瘤细胞系，并通过细胞计数测量增殖情况。吲哚美辛、对乙酰氨基酚、舒林酸硫化物和NS-398（N-[2-环己氧基)-4-硝基苯基]甲磺酰胺）对C6大鼠胶质瘤细胞增殖诱导了时间和浓度依赖性抑制。化学结构不相关的NSAIDs对COX的抑制导致大鼠和人胶质瘤细胞增殖受到抑制。四氮唑还原试验（MTT）表明吲哚美辛诱导细胞活力降低。用荧光底物检测，所测试的NSAIDs均未诱导半胱天冬酶-3/7激活。使用c-Src抑制剂PP2和MEK抑制剂PD 098059可消除吲哚美辛诱导的C6细胞增殖抑制，提示存在不依赖COX的机制。吲哚美辛降低了S期细胞的百分比，G0/G1期和/或G2/M期相对增加。NSAIDs可能在胶质瘤的药物干预中具有重要临床意义。
