Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents.
Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents.
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DOI：
10.1093/jnci/94.23.1745
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发表时间：
2002-12
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影响因子：
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通讯作者：
Jiuxiang Zhu;Xueqin Song;Ho-pi Lin;D. Young;Shunqi Yan;V. Marquez;Ching S. Chen
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文献类型：
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作者：
Jiuxiang Zhu;Xueqin Song;Ho-pi Lin;D. Young;Shunqi Yan;V. Marquez;Ching S. Chen
环氧化酶-2（考克斯-2）抑制剂塞来昔布被认为是通过使癌细胞对凋亡信号敏感而起化学预防剂的作用。其他考克斯-2抑制剂，如罗非昔布，在诱导细胞凋亡方面比塞来昔布弱两个数量级。塞来昔布和罗非昔布的分子结构被用作起点，以检查导致这种差异的结构特征。方法我们采用系统的化学方法对塞来昔布和罗非昔布进行结构修饰，以产生一系列化合物，测试其对人前列腺癌PC-3细胞活力的影响及其诱导这些细胞凋亡的能力。通过台盼蓝染料排除试验测量细胞活力，通过定量DNA切割的酶联免疫吸附试验和通过聚（ADP-核糖）聚合酶（PARP）切割的蛋白质印迹检测来测量细胞凋亡。蛋白质印迹法用于监测化合物对丝氨酸/苏氨酸激酶Akt和细胞外信号调节激酶2（ERK 2）（塞来昔布诱导的细胞凋亡信号的两种组分）磷酸化的影响。蒙特卡罗模拟用于对选定化合物的表面静电势和电子密度进行分子建模。所有统计检验均为双侧检验。结果诱导PC-3细胞凋亡的结构要求与抑制考克斯-2的结构要求不同。结构-功能分析表明，诱导凋亡的化合物来自考克斯-2抑制剂需要一个庞大的终端苯环，一个杂环系统与负静电势，和苯磺酰胺或苯甲酰胺部分。这些衍生物通过促进Akt和ERK 2的去磷酸化来介导细胞凋亡，而不管它们的考克斯-2抑制活性如何。结论通过修饰现有的考克斯-2抑制剂，可以合成一类新的以Akt和ERK 2信号通路为靶点诱导前列腺癌细胞凋亡的化合物。
BACKGROUND The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Other COX-2 inhibitors, such as rofecoxib, are two orders of magnitude less potent than celecoxib at inducing apoptosis. The molecular structures of celecoxib and rofecoxib were used as starting points to examine the structural features that contribute to this discrepancy. METHODS We used a systematic chemical approach to modify the structures of celecoxib and rofecoxib to produce a series of compounds that were tested for their effects on the viability of human prostate cancer PC-3 cells and their ability to induce apoptosis in these cells. Cell viability was measured by the trypan blue dye exclusion assay, and apoptosis was measured by an enzyme-linked immunosorbent assay that quantifies DNA cleavage and by western blot detection of poly(ADP-ribose) polymerase (PARP) cleavage. Western blotting was used to monitor the effects of the compounds on phosphorylation of the serine/threonine kinase Akt and extracellular signal-regulated kinase 2 (ERK2), two components of celecoxib-induced apoptosis signaling. Monte Carlo simulations were used to molecularly model the surface electrostatic potential and electron density of selected compounds. All statistical tests were two-sided. RESULTS The structural requirements for the induction of apoptosis in PC-3 cells were different from those for COX-2 inhibition. Structure-function analysis indicated that the induction of apoptosis by compounds derived from COX-2 inhibitors required a bulky terminal phenyl ring, a heterocyclic system with negative electrostatic potential, and a benzenesulfonamide or benzenecarboxamide moiety. These derivatives mediated apoptosis by facilitating the dephosphorylation of Akt and ERK2, irrespective of their COX-2 inhibitory activities. CONCLUSION A new class of compounds that induce apoptosis by targeting Akt and ERK2 signaling pathways in human prostate cancer cells can be synthesized by modifying existing COX-2 inhibitors.