John-Aryankalayil Molykutty, Palayoor Sanjeewani T, Cerna David, Falduto Michael T, Magnuson Scott R, Coleman C Norman
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 9000 Rockville Pike, Room B3 B 406, Building 10, Bethesda, MD 20892, USA.
Mol Cancer Ther. 2009 Jan;8(1):261-73. doi: 10.1158/1535-7163.MCT-08-0928.
Cyclooxygenase-2 (COX-2) plays a significant role in tumor development and progression. Nonsteroidal anti-inflammatory drugs (NSAID) exhibit potent anticancer effects in vitro and in vivo by COX-2-dependent and COX-2-independent mechanisms. In this study, we used microarray analysis to identify the change of expression profile regulated by a COX-2-specific NSAID NS-398 (0.01 and 0.1 mmol/L), a nonspecific NSAID ibuprofen (0.1 and 1.5 mmol/L) and RNA interference (RNAi)-mediated COX-2 inhibition in PC3 prostate cancer cells. A total of 3,362 differentially expressed genes with 2-fold change and P<0.05 were identified. Low concentrations of NSAIDs and COX-2 RNAi altered very few genes (1-3%) compared with the higher concentration of NS-398 (17%) and ibuprofen (80%). Ingenuity Pathway Analysis was used for distributing the differentially expressed genes into biological networks and for evaluation of functional significance. The top 3 networks for both NSAIDs included functional categories of DNA replication, recombination and repair, and gastrointestinal disease. Immunoresponse function was specific to NS-398, and cell cycle and cellular movement were among the top functions for ibuprofen. Ingenuity Pathway Analysis also identified renal and urologic disease as a function specific for ibuprofen. This comprehensive study identified several COX-2-independent targets of NSAIDs, which may help explain the antitumor and radiosensitizing effects of NSAIDs. However, none of these categories were reflected in the identified networks in PC3 cells treated with clinically relevant low concentrations of NS-398 and ibuprofen or with COX-2 RNAi, suggesting the benefit to fingerprinting preclinical drug concentrations to improve their relevance to the clinical setting.
环氧化酶-2（COX-2）在肿瘤发生和发展过程中发挥着重要作用。非甾体抗炎药（NSAID）通过COX-2依赖性和COX-2非依赖性机制在体外和体内均表现出强大的抗癌作用。在本研究中，我们利用基因芯片分析来确定COX-2特异性非甾体抗炎药NS-398（0.01和0.1 mmol/L）、非特异性非甾体抗炎药布洛芬（0.1和1.5 mmol/L）以及RNA干扰（RNAi）介导的COX-2抑制作用对PC3前列腺癌细胞中基因表达谱的影响。共鉴定出3362个差异表达基因，其变化倍数为2倍且P<0.05。与较高浓度的NS-398（17%）和布洛芬（80%）相比，低浓度的非甾体抗炎药和COX-2 RNAi改变的基因很少（1 - 3%）。利用 Ingenuity 通路分析将差异表达基因分配到生物网络中，并评估其功能意义。两种非甾体抗炎药的前三大网络均包括DNA复制、重组和修复以及胃肠道疾病等功能类别。免疫反应功能是NS-398所特有的，而细胞周期和细胞运动是布洛芬的主要功能之一。Ingenuity 通路分析还确定肾脏和泌尿系统疾病是布洛芬特有的功能。这项综合性研究确定了几种非甾体抗炎药的COX-2非依赖性靶点，这可能有助于解释非甾体抗炎药的抗肿瘤和放射增敏作用。然而，在用临床相关低浓度的NS-398和布洛芬或COX-2 RNAi处理的PC3细胞中，这些类别均未在鉴定出的网络中体现，这表明对临床前药物浓度进行指纹识别以提高其与临床情况的相关性具有益处。
