Effects Of Celecoxib On Drug Resisitance Of Gastric Cancer Cells And Analysis Of Its Potential Mechanism

Background and Objective:Apoptosis resisitance is one major mechanism of drug resistance which is an important reason for the failure of chemotherapy.NF-κB can be activated following chemotherapy, which could lead to upregulation of inhibitor of apoptosis proteins family (IAPs).Maybe this signal pathway is one of the mechanisms in drug resistance.Livin and Survivin are new members of IAPs with great anti-apoptosis effect.The overexpression of Livin and Survivin has been observed in many cancers,which is implied that Livin and Survivin may be involved in the development of cancers.But whether Livin and Suvivin in combination with NFκB are involved in drug resistance after chemotherapy especially in gastric cancer has not been clearly addressed. Gastric cancer is one of the most common malignacies in our country. The major therapeutic methods for gastric cancer are surgery and chemotherapy.Drug resistance is the major reason for the failure of chemotherapy ultimately and should be resolved urgently.Celecoxib,one cylooxygenase-2(COX-2)inhibitor,has been used in osteoarthritis and rheumarthritis.It can also inhibit the proliferation of gastric cancer cells and prevent NF-κB from activation which was identified in NSCLC.The aim of our study was to investigate the relationship between activation of NF-κB,expression of Livin and Survivin and drug resistance in gastric carcinoma SGC7901 and SGC7901/VCR cells.The second aim was to investigate the effect of celecoxib on proliferation and apoptosis,as well as on NF-κB activation and the expression of Livin and Survivin.Methods:Gastric cancer cell line(SGC7901)and the cell line resistance to VCR(SGC7901/VCR)were cultured in vitro.The proliferation and apoptosis of gastric cancer cells after drug(VCR,celecoxib)were detected by MTT and flow cytometry.Activation of NF-κB transcription was analyzed by ELISA.Protein expression of Livin,Survivin and NF-κB were assessed by Western blot technique.Results:The inhibition of proliferation was reduced in SGC7901/VCR cells after been exposed to VCR,and the ratio of apoptosis was also decreased.The content of NF-κB p65 in nuclear of SGC7901/VCR cells was significantly increased(0.404±0.025)when compared with that of SGC7901 cells(0.301±0.016)(P＜0.01).Livin and Survivin were also overexpressed in SGC7901/VCR cells(P＜0.05).Celecoxib could inhibit the expression of Livin and Survivin in SGC7901/VCR cells and enhance the effect of VCR cytotoxicity.The inhibition of proliforation and induction of apoptosis were increased in SGC7901/VCR after the treatment of celecoxib combind with VCR.Conclusions:The activation of NF-κB and upregulation of Livin and Survivin may be involved in the process of drug resistance of SGC7901 cells.Upregulation of Livin and Survivin might relate to activation of NF-κB.Celecoxib can inhibit the expression of Livin and Survivin,and increase the chemosensitivity of SGC7901/VCR cells to VCR,which might be the mechanism of drug resistance reversal by celecoxib in gastric cancer cells.