Novel selective Cox-2 inhibitors induce apoptosis in Caco-2 colorectal carcinoma cell line
Novel selective Cox-2 inhibitors induce apoptosis in Caco-2 colorectal carcinoma cell line
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DOI：
10.1016/j.ejps.2011.09.005
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发表时间：
2011-11-20
影响因子：
4.6
通讯作者：
Behravan, Javad
中科院分区：
文献类型：
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作者：
Heravi, Reza Entezari;Hadizadeh, Farzin;Behravan, Javad
环氧合酶-2(COX-2)抑制剂包括塞来昔布，可抑制细胞生长并诱导癌细胞凋亡。由于COX-2在结直肠癌等实体瘤中过度表达，因此可以作为癌症治疗研究的合适靶点。本研究设计合成了新型环氧合酶-2抑制剂4，5-双芳基咪唑基咪唑类化合物，并对其诱导细胞凋亡的活性进行了评价。用比色法测定我们合成的化合物对绵羊COX-1和COX-2的抑制能力。用四甲基偶氮唑盐比色法检测COX-2抑制剂和塞来昔布对Caco-2细胞增殖的影响。用流式细胞仪和DNA片段分析法检测细胞凋亡率。利用基因芯片技术研究这些化合物对112个细胞凋亡相关基因的影响。用实时定量聚合酶链式反应检测5种细胞凋亡相关基因Bak-1、Bclx、BIRC(Survivin)、TNFSF10和CASP3的表达。在我们合成的化合物(3a-c)中，4，5-二(4-甲氧基苯基)-1H-咪唑-2-基衍生物(化合物3c)显示出最高的COX-1/COX-2选择性指数(SI=262.9)和最低的生长抑制浓度(IC(50)=21.20mM)。此外，化合物3a-c还可以上调促凋亡基因，下调抗凋亡基因。因此，这些合成的化合物似乎是Caco-2细胞系的凋亡诱导剂。本研究表明，4，5-双芳基咪唑咪唑是设计COX-2抑制剂的理想支架材料，4，5-二(4-甲氧基苯基)-1H-咪唑-2-基衍生物比塞来昔布具有更高的COX-2抑制活性和选择性。提示其具有诱导Caco-2结直肠癌细胞凋亡的作用。(C)2011爱思唯尔B.V.保留所有权利。
The cyclooxygenase-2 (COX-2) inhibitors including celecoxib inhibit cell growth and induce apoptosis in cancer cells. As COX-2 is over expressed in solid tumors such as colorectal cancer, it can be a suitable target for cancer treatment studies. In this study we designed and synthesized 4,5-bisaryl imidazolyl imidazoles as novel COX-2 inhibitors and evaluated their apoptosis inducing activities. The ability of our synthetic compounds to inhibit ovine COX-1 and COX-2 was determined using a colorimetric method. The effects of these COX-2 inhibitors and celecoxib on the proliferation of Caco-2 cells were evaluated by MTT assay. Cell apoptosis was determined by flow cytometry and DNA fragmentation assay. cDNA microarray technique was used to evaluate the effects of these synthetic compounds on 112 genes involved in apoptosis pathways. The expression of five apoptosis-related genes Bak-1, Bcl-x, BIRC (Survivin), TNFSF10 and CASP3 were evaluated by quantitative real-time PCR. Among our synthetic compounds (3a-c), 4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl derivative (compound 3c) exhibited the highest COX-1/COX-2 selectivity index (SI = 262.9) and lowest growth inhibitory concentration (IC(50) = 21.20 mu M). In addition, compounds 3a-c could up-regulate pro-apoptotic genes and down-regulate anti-apoptotic genes. So, these synthetic compounds seem to be inducers of apoptosis in Caco-2 cell line. This study indicates that 4,5-bisaryl imidazolyl imidazole is a suitable scaffold to design COX-2 inhibitors and 4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl derivative exhibited highly COX-2 inhibitory potency and selectivity even more than celecoxib. It seems that it could induce apoptosis in Caco-2 colorectal carcinoma cell line. (C) 2011 Elsevier B.V. All rights reserved.