COX-2特异性抑制剂NS-398对胰腺癌生长及肿瘤血管生成影响

目的:探讨COX-2特异性抑制剂NS-398对胰腺癌生长的影响及其机制。方法:分别用q RT-PCR与Western blot检测不同人胰腺癌细胞株(Bx PC-3、SWl990、Capan-2、Aspc-1、PANC-1)中COX-2及VEGF表达,并用MTT法检测NS-398在体外对人胰腺癌细胞增殖抑制作用;用体外实验最敏感细胞株建立裸鼠胰腺癌原位移植瘤模型,并随机将荷瘤鼠分为实验组和对照组,分别用NS-398与生理盐水处理,比较两组移植瘤的生长情况,并检测肿瘤组织中COX-2、VEGF蛋白表达及肿瘤微血管密度(MVD)。结果:各胰腺癌细胞中均有COX-2及VEGF表达,NS-398呈时间与浓度依赖性抑制各胰腺癌细胞的体外增殖,其中Bxpc-3细胞COX-2与VEGF表达量最高,且对NS-398最敏感。用Bxpc-3细胞建立原位移植瘤的实验组与对照组裸鼠比较,平均肿瘤体积明显减小(20.215 2 mm~3 vs.204.444 4 mm~3),瘤组织中COX-2与VEGF表达及MVD均明显降低(均P0.05)。结论:NS-398对胰腺癌的生长有抑制作用,其机制可能是通过COX-2途径降低VEGF基因表达从而抑制肿瘤血管生成有关。

Influence of COX-2 specific inhibitor NS-398 on growth and tumor angiogenesis of pancreatic cancer

Objective: To investigate the influence of COX-2 specific inhibitor NS-398 on growth of pancreatic cancer and its mechanism. Methods: The expressions of COX-2 and VEGF in different human pancreatic cancer cell lines (BxPC-3, SWl990, Capan-2, Aspc-1, PANC-1) were determined by qRT-PCR and Western blot respectively, and the inhibitory effects of NS-398 on proliferation of each pancreatic cancer cell line in vitro were measured by MTT assay. Orthotopic transplantation models of pancreatic cancer using the most sensitive cell line identified by in vitro tests were established in nude mice, and then the tumor-bearing mice were randomly divided into experimental group and control group, which underwent treatment with NS-398 or normal saline respectively. The growths of the tumor xenografts in the two groups were compared and the expressions of COX-2 and VEGF protein as well as microvessel density (MVD) in the tumor tissues were detected. Results: All the pancreatic cancer cell lines presented COX-2 and VEGF expressions with varying degrees; NS-398 inhibited the in vitro proliferation of all the pancreatic cancer cells in time- and concentration-dependent manner, and among them, Bxpc-3 cells had the highest expression levels of COX-2 and VEGF, and were also most sensitive to NS-398. After establishment of orthotopic pancreatic cancer model with Bxpc-3 cells, in mice in experimental group compared with those in control group, the average tumor volume was significantly reduced (20.215 2 mm3 vs. 204.444 4 mm3), and the expression levels of COX-2 and VEGF as well as MVD were all significantly reduced (all P<0.05).Conclusion: NS-398 has inhibitory effect on growth of pancreatic cancer, and the mechanism may be related to its decreasing VEGF gene expression via COX-2 pathway and thereby reducing tumor angiogenesis.