Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells.
Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells.
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DOI：
10.1093/jnci/94.8.585
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发表时间：
2002-04
期刊：
影响因子：
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通讯作者：
Xueqin Song;Ho-pi Lin;A. Johnson;Ping-Hui Tseng;Ya-Ting Yang;S. Kulp;Ching S. Chen
中科院分区：
文献类型：
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作者：
Xueqin Song;Ho-pi Lin;A. Johnson;Ping-Hui Tseng;Ya-Ting Yang;S. Kulp;Ching S. Chen
背景
环氧化酶 - 2（COX - 2）抑制剂的抗肿瘤活性被认为涉及COX - 2酶抑制和细胞凋亡诱导，但尚不清楚细胞凋亡是否需要COX - 2抑制。不同的COX - 2抑制剂对COX - 2抑制具有相似的半数抑制浓度（IC₅₀值），但在诱导细胞凋亡的能力上差异很大，这表明细胞凋亡存在不依赖COX - 2的途径。为了验证这一假设，我们研究了COX - 2缺失对细胞凋亡的影响，并对雄激素非依赖性前列腺癌细胞系PC - 3中COX - 2抑制剂塞来昔布进行了构效分析。
方法
分离出四环素诱导（Tet - On）的COX - 2反义克隆，以评估COX - 2表达对细胞活力以及对COX - 2抑制剂诱导的细胞凋亡敏感性的影响。未经处理的Tet - On克隆COX - 2表达不同，经多西环素处理的克隆COX - 2缺失。我们合成并表征了具有不同COX - 2抑制活性的各种塞来昔布衍生物，并测定了它们在PC - 3细胞中的凋亡活性。通过四项测试评估细胞凋亡。
结果
与诱导细胞凋亡的COX - 2抑制剂的作用相反，COX - 2缺失并未诱导细胞死亡。对COX - 2抑制剂诱导的细胞凋亡的敏感性与COX - 2表达水平无关。构效分析发现细胞凋亡诱导与COX - 2抑制之间没有相关性。一些缺乏COX - 2抑制活性的塞来昔布衍生物促进了细胞凋亡，反之亦然。此外，塞来昔布和具有凋亡活性的塞来昔布衍生物通过抑制相同的途径介导细胞死亡。
结论
我们通过对COX - 2抑制剂塞来昔布进行结构修饰，将诱导细胞凋亡的活性与COX - 2抑制活性分离开来。这种活性的分离可能为开发新型细胞凋亡诱导剂提供分子基础。
BACKGROUND The antitumor activity of cyclooxygenase-2 (COX-2) inhibitors is thought to involve COX-2 enzyme inhibition and apoptosis induction, but it is unclear whether COX-2 inhibition is required for apoptosis. Different COX-2 inhibitors have similar IC(50) values (concentration for 50% inhibition) for COX-2 inhibition but differ considerably in their abilities to induce apoptosis, suggesting the involvement of a COX-2-independent pathway in apoptosis. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis and performed a structure-activity analysis of the COX-2 inhibitor celecoxib in the androgen-independent prostate cancer cell line PC-3. METHODS Tetracycline-inducible (Tet-On) COX-2 antisense clones were isolated to assess the effect of COX-2 expression on cell viability and sensitivity to apoptosis induced by COX-2 inhibitors. Untreated Tet-On clones differentially expressed COX-2, and doxycycline-treated clones were depleted of COX-2. We synthesized and characterized various celecoxib derivatives with various COX-2 inhibitory activities and determined their apoptotic activity in PC-3 cells. Apoptosis was assessed with four tests. RESULTS In contrast to the effect of COX-2 inhibitors, which induced apoptosis, COX-2 depletion did not induce cell death. Susceptibility to COX-2 inhibitor-induced apoptosis was independent of the level of COX-2 expression. Structure-activity analysis found no correlation between apoptosis induction and COX-2 inhibition. Some celecoxib derivatives that lacked COX-2 inhibitory activity facilitated apoptosis and vice versa. Moreover, celecoxib and apoptosis-active celecoxib derivatives mediated cell death by inhibiting the same pathway. CONCLUSION We have dissociated the apoptosis-inducing activity from the COX-2 inhibitory activity by structural modifications of the COX-2 inhibitor celecoxib. This separation of activities may provide a molecular basis for the development of new classes of apoptosis-inducing agents.