Losartan Enhances The Sensitivity Of Gastric Cancer Cells To XELOX Chemotherapy And Related Mechanisms

Objective:Epidemiological studies have found that angiotensin II receptor blockers(ARB)may have anti-tumor effects.The XELOX chemotherapy regimen(capecitabine+ oxaliplatin),as the current first-line chemotherapy regimen for gastric cancer,is prone to rapid drug resistance.This study aimed to investigate whether the ARB drug Losartan can enhance the sensitivity of gastric cancer cells to XELOX chemotherapy and its possible mechanism.Methods:In vitro,we used capecitabine prodrug 5-FU combined with oxaliplatin as the XELOX chemotherapy regimen,and set up the control group,the losartan group,the XELOX group(5-FU+oxaliplatin)and the combination group(losartan+XELOX)treat gastric cancer cells,detect their proliferation,migration and invasion ability,selfrenewal ability and related signal channel proteins(Ki-67,E-cadherin,MMP2,CD44,C-myc,Nanog)changes.In vivo,capecitabine(5-FU prodrug)was used instead of 5FU,combined with oxaliplatin as the XELOX chemotherapy regimen,to evaluate the tumor size and weight change of each group of nude mice after treatment.Immunohistochemistry was used to detect changes in the expression levels of the above-mentioned proteins in transplanted tumors,and to evaluate the effects of different drugs on the liver of nude mice.Results:In vitro,although losartan(<10μM)alone had a weak inhibitory effect on the proliferation of gastric cancer cells when acting on different gastric cancer cells,it could significantly enhance the proliferation inhibitory effect of XELOX on MGC803 and MKN45(p<0.001),and its inhibitory effect on cell migration,invasion and selfrenewal ability of gastric cancer stem cells(p<0.001);In vivo,we found that the tumor size of mice treated with losartan(1Omg/kg)alone or XELOX(CAP 180mg/kg+L-OHP 5mg/kg)was significantly smaller than that of the control group(0.9%saline)(p<0.05),while there was no significant difference between the Losartan group and XELOX group(p>0.05);in addition,the combination group(Losartan 10mg/kg+CAP 180mg/kg+L-OHP 5mg/kg)was significantly smaller than that of the XELOX group(p<0.05).The body weight growth curve showed that there was no significant difference in the body weight of the mice between the treatment groups,and the HE staining indicated that the liver damage of the mice in the combination group was less than that in the XELOX group alone.Western blot and IHC results showed that the expressions of Ki-67 and MMP-2 were significantly reduced in the cells and tumor tissues treated by the combination group,and the expression of E-cadherin,the key protein of epithelial-mesenchymal transition(EMT),was up-regulated;the expression of markers CD44,and the self-renewing proteins C-myc and Nanog of cancer stem cells were down-regulated in gastric cancer cells and tumor tissues.Conclusion:Losartan can significantly improve the sensitivity of gastric cancer cells to XELOX chemotherapy,and greatly enhance the inhibitory effect of XELOX on the growth,migration and invasion of gastric cancer cells and the stemness of gastric cancer stem cells.Additionally,it will not increase the side effects of XELOX chemotherapy.These effects may be achieved by inhibiting self-renewal of gastric cancer stem cell,tumor angiogenesis,and epithelial-mesenchymal transition.This study provides theoretical and experimental basis for the clinical use of Losartan as a chemotherapeutic sensitizer to improve the therapeutic effect of XELOX.