胰腺癌组织COX-2、VEGF、MMP-9的表达及塞来布昔对人胰腺癌BXPC-3细胞VEGF、MMP-9表达的影响

目的观察胰腺癌组织环氧合酶-2(COX-2)、血管内皮生长因子(VEGF)、基质金属蛋白酶-9(MMP-9)的表达及塞来布昔对人胰腺癌BXPC-3细胞VEGF、MMP-9表达的影响。方法采用免疫组织化学SP法检测COX-2、VEGF、MMP-9在50例原发性胰腺癌及癌旁正常组织的表达,分析其与胰腺癌临床病理特征的关系。实时荧光定量PCR法(RT-QPCR)和Western blot检测塞来布昔对BXPC-3细胞VEGF、MMP-9 mRNA和蛋白表达的影响。结果COX-2、VEGF、MMP-9在胰腺癌组织的阳性表达率显著高于癌旁组织,差异有统计学意义(P<0.05)。COX-2、VEGF、MMP-9高表达与胰腺癌增殖活性、TNM临床分期及肿瘤浸润转移等临床病理特征相关(P<0.05),而与年龄、性别、发病部位、病理组织分级无关(P>0.05);且COX-1与VEGF、MMP-9表达呈正相关性(P<0.05)。随着塞来布昔剂量的增高,BXPC-3细胞VEGF、MMP-9 mRNA和蛋白表达均降低,与对照组比较差异有统计学意义(P<0.05)。结论 COX-2、VEGF、MMP-9胰腺癌组织表达增高,可能在肿瘤发生发展中发挥重要作用;COX-2特异性抑制剂塞来布昔可能通过下调VEGF、MMP-9的表达发挥抗肿瘤作用。

Celecoxib enhances the detoxification of diethylnitrosamine in rat liver cancer

AIM： To study the effect of celecoxib （CXB） on diethylnitrosamine activation through the regulation of cytochrome P450 in a hepatocarcinogenesis model.METHODS： Six-week-old male Sprague-Dawley rats were randomly divided into five groups, a non-treated group （NT）, a diethylnitrosamine-treated group （DEN）, a DEN＋CXB-treated group （DEN＋CXB）,and CXB 8 d-treated and CXB 32 d-treated groups. The effects of celecoxib on the enzymatic activities of CYP1A1, 2A, 2B1/2, and 2E1 were assessed in hepatic microsomes 24 h after DEN administration.Changes in CYPIA1 and CYP2B1/2 protein expression were also evaluated. The rate of DEN metabolism was measured by the production of the deethylation metabolite acetaldehyde, and the denitrosation metabolite nitrite.RESULTS： DEN＋CXB administration produced a significant increase in the enzymatic activities ofCYP2B1/2 and 1A1, whereas it did not change the activities of CYP2A and 2E1, compared to that of the DEN group. CXB treatment for eight days did not produce a significant effect on enzymatic activity when compared to the NT group; however, when it was administered for prolonged times （CXB 32 d group）,the enzymatic activities were increased in a similar pattern to those in the DEN＋CXB group. The observed increase in the enzymatic activities in the DEN＋CXB group was accompanied by an increase in the CYP2B1/2 protein levels; no changes were observed in the levels of CYPIA1. In vitro, CXB increased the denitrosation of DEN, a pathway of metabolic detoxification. The addition of SKF-525A, a preferential inhibitor of CYP2B, abrogated the denitrosation of DEN.CONCLUSION： These results suggest that the mechanism of action of CXB involves enhancement of the detoxification of DEN by an increasing denitrosation via CYP2B1/2.

Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation

Selective cyclooxygenase-2 （COX-2） inhibitors are widely used due to their efficacy and good safety profile. However, recent case reports have described varying degrees of liver injudes associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.

Inhibitory effect of celecoxib combined with cisplatin on growth of human tongue squamous carcinoma Tca8113 cell xenograft tumor

Objective:The aim of this study was to observe the inhibitory effect of application of COX-2 inhibitor,celecoxib,combined with cisplatin on the growth of human tongue squamous carcinoma Tca8113 cell xenograft by animal experiment.Methods:The nude mice were transplanted subcutaneously with Tca 8113 cells,and then were administrated with celecoxib,cisplatin or celecoxib combined with cisplatin respectively,and were sacrificed after 35 days.The weight of xenograft was measured to calculate the tumor inhibition rate.The histological change was studied under light and electron microscope.The COX-2 protein expression was observed by immunohistological staining.And the COX-2 mRNA expression was determined by RT-PCR.Results:Celecoxib,the COX-2 inhibitor,could not only inhibit the growth of Tca8113 cell xenograft tumor and COX-2 protein expression,but also enhance the inhibitory effect cisplatin on xenograft tumor growth significantly.The tumor inhibition rates of celecoxib group,cisplatin group and celecoxib plus cisplatin group were 15.63%,37.50% and 82.81% respectively that was statistically significant compared to control group(P < 0.01).The combined application of celecoxib and cisplatin could inhibit tumor growth more significantly than that of separated application(P < 0.01).The inhibitory effect of celecoxib on COX-2 mRNA expression of Tca 8113 cell was weaker and not significant(P = 0.073).Conclusion:Celecoxib can not only inhibit xenograft tumor growth in nude mice,but also enhance the inhibitory effect of CDDP on Tca 8113 transplanted tumor growth in nude mice.The mechanism maybe related to inhibition of COX-2 protein expression,which offers beneficial reference to further explore the mechanism between inhibition of COX-2 enzyme activity and prevention of head and neck tumor.

Local effect of celecoxib on peripheral nerve repair com- bined with silicone tubulization in rat

Objective： To assess local effect of celecoxib on nerve regeneration in a rat sciatic nerve transec- tion model. Methods： Forty-five male healthy white Wistar rats were randomly divided into three experimental groups （n= 15 for each）： sham-operation （SHAM）, control （SIL） and celecoxib treated （SIL/CLX） groups. In SHAM group after anesthesia left sciatic nerve was exposed and after homeo- stasis muscle was sutured. In SIL group the left sciatic nerve was exposed in the same way and transected proximal to tibioperoneal bifurcation leaving a 10 mm gap. Proximal and distal stumps were each inserted into a silicone tube and filled with 10 gl phosphate buffered solution. In SIL/CLX group defect was bridged using a silicone tube filled with 10 μl celecoxib （0.1 g/L）. Results： Functional study and gastrocnemius muscle mass confirmed faster and better recovery of regenerated axons in SIL/CLX than in SIL group （P〈0.05）. Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers in SIL/CLX were significantly greater than those in control group. In immunohistochemistry, lo- cation of reactions to S-100 in SIL/CLX was clearly more positive than that in SIL group. Conclusion： Response to local treatment ofcelecoxib demonstrates that it influences and improves functional re- covery of peripheral nerve regeneration.