Differential effects of selective COX-2 inhibitors on cell cycle regulation and proliferation of glioblastoma cell lines
Differential effects of selective COX-2 inhibitors on cell cycle regulation and proliferation of glioblastoma cell lines
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DOI：
10.4161/cbt.3.1.571
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发表时间：
2004-01-01
影响因子：
3.6
通讯作者：
Schönthal, AH
中科院分区：
文献类型：
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作者：
Kardosh, A;Blumenthal, M;Schönthal, AH
众所周知，抑制环氧化酶（考克斯）I和考克斯-2的传统NSAID具有降低结直肠癌风险的潜力。新一代的考克斯抑制剂已经被开发出来，其选择性地抑制考克斯-2，这可能导致较少的副作用，同时仍然保留其治疗潜力。由于脑肿瘤患者，如胶质母细胞瘤，表现出非常差的预后，我们开始探索考克斯抑制剂是否可用于治疗这种类型的肿瘤。我们发现塞来昔布在体外抑制各种胶质母细胞瘤细胞系的增殖比传统的NSAID更有效。此外，尽管几种不同的选择性考克斯-2抑制剂有效地降低了这些细胞中的PGE 2水平，但它们都没有产生与塞来昔布相当的抗增殖作用。塞来昔布处理的细胞中加入外部PGE 2不能恢复增殖，表明塞来昔布的生长抑制不是通过阻断PGE 2产生介导的。为了确定可能介导塞来昔B有效抗增殖作用的潜在分子过程，我们发现细胞周期蛋白依赖性激酶（细胞增殖的基本调节因子）的活性丧失，这是由于细胞周期蛋白A和细胞周期蛋白B表达的转录下调。综上所述，我们的研究结果表明，塞来昔布对胶质母细胞瘤细胞生长具有考克斯-2非依赖性抗增殖作用，其作用强于其他选择性考克斯-2抑制剂或传统NSAID，并且通过细胞周期机制的两种基本组分细胞周期蛋白A和细胞周期蛋白B的转录抑制介导。
It is well established that traditional NSAIDs, which inhibit cyclooxygenase (COX) I and COX-2, have the potential to reduce the risk of colorectal cancer. New generation COX inhibitors have been developed that selectively inhibit COX-2, which might cause less side effects while still retaining their therapeutic potential. As patients with brain tumors, such as glioblastoma, exhibit a very poor prognosis, we began to explore whether COX inhibitors could be useful for the treatment of this type of tumor. We found that celecoxib inhibited the proliferation of various glioblastoma cell lines in vitro much more potently than traditional NSAIDs. In addition, although several different selective COX-2 inhibitors potently reduced PGE2 levels in these cells, none of them exerted anti-proliferative effects that were comparable to celecoxib. The addition of external PGE2 to celecoxib-treated cells did not restore proliferation, indicating that growth inhibition by celecoxib was not mediated via the blockage of PGE2 production. In an effort to determine the underlying molecular processes that might mediate celecoxib's potent anti-proliferative effects, we found a loss of the activity of cyclin-dependent kinases, the essential regulators of cell proliferation, which was due to the transcriptional downrequlation of cyclin A and cyclin B expression. Taken together, our results show that celecoxib exerts COX-2-independent anti-proliferative effects on glioblastoma cell growth, which are more potent than those of other selective COX-2 inhibitors or traditional NSAIDs, and which are mediated via the transcriptional inhibition of two essential components of the cell cycle machinery, cyclin A and cyclin B.