Study On The Sensitization Effect Of Esomeprazole To Paclitaxel Chemotherapy In Epithelial Ovarian Cancer Cells

Background and aims:Thelatestresearchindicates: acidic microenvironmenthasrelated toresistanceto chemotherapy.Proton pump inhibitors(PPIs)on the one hand,restrain the activity of vaculolar ATPaseso as to reverse the transembran PH gradient of tumor cells,on the other hand,inhibit tumor cell autophagy and promote its apoptosis,and thus improve the sensitivity of chemotherapy drugs.The aim of this study was investigated whether non-specific proton pumpinhibitors esomeprazole(EMSO)could increase the sensitivity of epithelial ovarian cancer(EOC)cells to paclitaxel(PTX)and the possible mechanisms.Methods: Immunohistochemical method for detecting the expression of vacuolar proton pump V-ATPase in epithelial ovarian carcinoma and normal ovarian tissues;EMSO alone and EMSO combined with Taxol in epithelial ovarian cancer sensitive cell line A2780 and drug-resistant A2780/T cell line :MTT and flow cytometry were used to detect cell survival and apoptosis.BCECF-AM,Caspase-3 spectrophotometry,Immunofluorescence microscope were used to detect the intracellular PH value,the activity of Caspase-3 and the distribution of GFP-LC3 fluorescent spot,respectively;Real Time-PCR and Western Blot were used to detect the expression of autophagy,drug resistance related genes and proteins.Result:Compared with the normal ovarian tissues,epithelial ovarian cancer tissues overexpressed V-ATPase,especially the cytoplasmic overexpression;Compared with paclitaxel sensitive cell A2780,paclitaxel resistant cell A2780/T had high intracellular PH and low extracellular PH,high expression of V-ATPase,autophagy and resistance to paclitaxel.Compared with paclitaxel alone,combined EMSO could significantly inhibit the proliferation of A2780/T cells and promote apoptosis,and this apoptosis is not related to the Caspase-3 pathway;Inhibition of autophagy,reversal of intracellular PH gradient and cell resistance phenotype(p < 0.05).Conclusions: Tumor acidification is produced during the proliferation of epithelial ovarian cancer cells;Chemotherapeutic agent induces cell protective autophagy;EMSO partially reverses the acidic microenvironment of epithelial ovarian cancer by inhibiting V-ATPase,prevents tumor cells from protecting autophagy and promotes apoptosis.So as to restore the sensitivity of ovarian cancer cells to paclitaxel.