Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition
Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition
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DOI：
10.1002/mc.20318
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发表时间：
2007-10-01
影响因子：
4.6
通讯作者：
Trask, Douglas K.
中科院分区：
文献类型：
--
作者：
Bock, Jonathan M.;Menon, Sarita G.;Trask, Douglas K.
本研究旨在比较10种不同的非甾体抗炎药（NSAID）在临床应用中的相对抗肿瘤活性，并研究其在头颈部鳞状细胞癌模型（SCCHN）中的潜在机制。使用标准的5天MTT试验计算10种NSAID在UM-SCC-1细胞中的IC 50值，包括塞来昔布、罗非昔布、舒林酸硫化物、舒林酸砜、吲哚美辛、酮洛芬、氟比洛芬、萘普生、吡罗昔康和阿司匹林。塞来昔布是一种考克斯-2特异性抑制剂，是迄今为止最有效的NSAID，IC 50为39.9 +/- 1.1 μ M，其次是舒林酸硫化物（116.5 +/- 2.34 μ M）。塞来昔布和舒林酸硫化物也比任何其他NSAID诱导更多的caspase-3活化。细胞周期分析显示，塞来昔布和硫舒林酸均诱导G期分布增加3倍，这与p21（waf 1/cip 1）的强烈诱导、细胞周期蛋白D1的抑制和Rb的低磷酸化相关。通过荧光素酶报告基因测定，塞来昔布和舒林酸硫化物处理诱导了对E2 F反式激活活性的强烈下游抑制。这些数据证明了各种NSAID药物的广泛活性，并揭示了通过细胞周期抑制和诱导细胞凋亡的作用机制。(c)2007 Wiley-Liss，Inc.
This study was performed to compare the relative antineoplastic activity of 10 different non-steroidal anti-inflammatory drugs (NSAIDs) in clinical use, and to investigate the underlying mechanisms of this activity in a squamous cell carcinoma of the head and neck model (SCCHN). A standard 5-day MTT assay was used to calculate IC50 values in UM-SCC-1 cells for 10 NSAIDs, including celecoxib, rofecoxib, sulindac sulfide, sulindac sulfone, indomethacin, ketoprofen, flurbiprofen, naproxen, piroxicam, and aspirin. Celecoxib, a COX-2 specific inhibitor, was by far the most potent NSAID, with an IC50 of 39.9 +/- 1.1 mu M, followed by sulindac sulfide (116.5 +/- 2.34 mu M). Celecoxib and sulindac sulfide also induced more activation of caspase-3 than any other NSAID. Cell cycle analysis showed that celecoxib and sulindac sulfide both induced a 3-fold increase in G, phase distribution, and this correlated with strong induction of p21(waf1/cip1), inhibition of cyclin D1, and hypophosphorylation of Rb. Celecoxib and sulindac sulfide treatment induced strong downstream inhibition of E2F transactivating activity as determined by a luciferase reporter assay. These data demonstrate the wide range of activity of various NSAID agents, and reveal a mechanism of action through cell cycle inhibition and induction of apoptosis. (c) 2007 Wiley-Liss, Inc.