CXCR4抑制剂AMD3100抑制结肠癌细胞奥沙利铂耐药的机制研究  

CXCR4 antagonist AMD3100 reduced oxaliplatin resistance in colorectal cancer cells

作　　者：韩刚[1] 曹羽[1] 张云[1] 张言言 张旭[1] 刘宁宁[2] 贾茹 龚航军[1] HAN Gang;CAO Yu;ZHANG Yun;ZHANG Yan-yan;ZHANG Xu;LIU Ning-ning;JIA Ru;GONG Hang-jun(Department of Gastrointestinal Surgery,Shuguang Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Department of Oncology,Shuguang Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)

机构地区：[1]上海中医药大学附属曙光医院胃肠外科,上海201203 [2]上海中医药大学附属曙光医院肿瘤科,上海201203

出　　处：《中国现代普通外科进展》2023年第12期939-942,共4页Chinese Journal of Current Advances in General Surgery

基　　金：上海中医药大学理科预算内项目(编号:2019LK019)。

摘　　要：目的:探讨CXCR4抑制剂AMD3100对奥沙利铂耐药的影响及其作用机制。方法:构建奥沙利铂耐药细胞HCT116;q-PCR和Western blot检测耐药组与对照组CXCR4表达及PI3K-AKT信号通路磷酸化水平。q-PCR和Western blot检测CXCR4抑制剂AMD3100刺激上述细胞系后PI3K-AKT信号通路磷酸化水平变化。CCK8检测AMD3100抑制CXCR4或联合应用AKT抑制剂LY294002对奥沙利铂耐药细胞的耐药性影响。结果:不同浓度奥沙利铂刺激后,耐药组细胞活性无显著变化,而对照组细胞活性随奥沙利铂浓度增加而显著下降。q-PCR和Western blot检测发现耐药组细胞CXCR4表达和PI3K-AKT磷酸化水平显著上升(P<0.05)。给予CXCR4抑制剂AMD3100后,CXCR4表达和PI3K-AKT磷酸化水平显著下降(P<0.05)。结论:CXCR4通过激活PI3K-AKT信号通路在结肠癌奥沙利铂耐药中发挥作用。AMD3100能够增强耐药细胞对奥沙利铂的敏感性,可能成为对抗结肠癌化疗耐药的潜在治疗药物。Objective:colorectal cancer is one of the common malignant tumors in the gastrointestinal tract.Oxaliplatin is the first-line drug for the treatment of advanced colorectal cancer,but drug resistance often occurs.The mechanism of CXCR4 in oxaliplatin resistance of colon cancer is not clear.This study intends to explore the mechanism of CXCR4 mediated oxaliplatin resistance and the potential therapeutic value of CXCR4 inhibitor AMD3100.Methods:oxaliplatin resistant strains HCT116 were constructed.The expression of CXCR4 and the phosphorylation level of PI3K-Akt signal pathway were detected by Q-PCR and Western blot.The phosphorylation level of PI3K-Akt signal pathway was detected by Q-PCR and Western blot.The effect of AMD3100 antagonizing CXCR4 or combined application of Akt inhibitor LY294002 on oxaliplatin resistance of drug-resistant cells was detected by CCK8.Results:CCK-8 was used to detect the proliferation activity of Oxaliplatin in HCT116 drug resistant group compared with control cells in the absence of drugs and at different concentrations.The results showed that there was no significant change in the activity of the resistant strains,while the control cells showed a significant decrease.Q-PCR and Western blot showed that the expression of CXCR4 and the phosphorylation level of PI3K-Akt increased significantly in the drug-resistant group(P<0.05).After administration of CXCR4 inhibitor AMD3100,CXCR4 expression and PI3K-Akt phosphorylation decreased significantly(P<0.05).AMD3100 enhanced the sensitivity of drug-resistant cell lines to oxaliplatin.The combination of AMD3100 and Akt inhibitor LY294002 can further enhance the sensitivity of drug-resistant cell lines to oxaliplatin.Conclusion:CXCR4 mediated activation of PI3K-Akt signaling pathway plays an important role in the resistance of colon cancer to oxaliplatin.AMD3100 may become a potential therapeutic drug against chemoresistance of colon cancer.

关 键 词：结肠肿瘤 奥沙利铂 化疗耐药 CXCR4 PI3K-AKT信号通路 

分 类 号：R735.35[医药卫生—肿瘤]