Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells
Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells
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DOI：
10.1002/ijc.23315
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发表时间：
2008-05-01
影响因子：
6.4
通讯作者：
Yang, Chung S.
中科院分区：
文献类型：
--
作者：
Xiao, Hang;Zhang, Qiang;Yang, Chung S.
先前在动物模型中的研究已经显示他汀类药物和非甾体抗炎药联合治疗对结直肠癌发展的增强功效。在我们的研究中，我们研究了阿托伐他汀和塞来昔布在2个人结肠癌细胞系HCT 116和HT 29中的联合作用。塞来昔布中度抑制两种细胞系的生长，IC 50为40-50 μ M，而阿托伐他汀在处理48-72小时后对HCT 116细胞的生长抑制作用强于HT 29细胞（IC 50为5-8 μ M vs. 30-35 μ M）。流式细胞仪分析表明，联合处理24小时引起广泛的细胞周期停滞在G 0/G1期，而在48小时或更长时间，诱导凋亡显着。联合用药产生的作用比单独使用阿托伐他汀或塞来昔布强得多。我们的研究结果进一步表明，阿托伐他汀/塞来昔布的联合作用与p21（Cip 1/Wafl）、p27（Kip 1）和磷酸化JNK水平升高、磷酸化AKT和过度磷酸化Rb水平降低以及caspase级联激活相关。阿托伐他汀/塞来昔布组合还选择性地修饰小G蛋白（如RhoA、RhoB和RhoC）的膜定位，这可能有助于抗癌作用。总之，结果表明阿托伐他汀和塞来昔布在抑制人结肠癌细胞生长和杀死人结肠癌细胞方面的作用之间具有很强的协同作用。目前的工作表明，这种组合的可能的治疗应用，并提供了在临床试验中的机制和生物标志物的调查线索。(C)2008 Wiley-Liss，Inc.
Previous studies in animal models have shown enhanced efficacy of a combined treatment of statins and Nonsteroidal anti-inflammatory drugs against colorectal cancer development. In our study, we investigated the combinational effects of atorvastatin and celecoxib in 2 human colon cancer cell lines HCT116 and HT29. Celecoxib moderately inhibited the growth of both cell lines with a similar IC50 of 40-50 mu M, whereas atorvastatin showed stronger growth inhibitory effect in HCT116 cells than in HT29 cells (IC50 of 5-8 mu M vs. 30-35 mu M) after treatment for 48-72 hr. The combination of these 2 agents produced strong synergistic actions, as determined by isobologram analysis. Flow cytometry analysis indicated that the combination treatment for 24 hr caused extensive cell cycle arrest in GO/G1 phase; whereas at 48 hr or longer, apoptosis was induced significantly. The effects produced by the combination were much stronger than that by atorvastatin or celecoxib alone. Our results further demonstrated that the combinational effects of atorvastatin/celecoxib were associated with increased levels of p21(Cip1/Wafl), p27(Kip1), and phospho-JNK; decreased levels of phospho-AKT and hyper-phosphorylated Rb; and activation of caspase cascade. Atorvastatin/celecoxib combination also selectively modified membrane localization of small G-proteins, such as RhoA, RhoB and RhoC, which may contribute to the anti-cancer effects. Taken together, the results demonstrated a strong synergy between the actions of atorvastatin and celecoxib in growth inhibition and killing of human colon cancer cells. The present work suggests the possible therapeutic application of this combination and provides leads for mechanistic and biomarker investigations in clinical trials. (C) 2008 Wiley-Liss, Inc.