阿瑞匹坦通过内质网应激逆转结直肠癌小鼠化疗耐药的机制研究  

Mechanism of aprepitant in reversing chemoresistance in colorectal cancer mice through endoplasmic reticulum stress

作　　者：陈绍兰 罗俊 彭书生 冉靖 游先辉[1] CHEN Shaolan;LUO Jun;PENG Shusheng;RAN Jing;YOU Xianhui(Department of Laboratory Medicine,Qingbaijiang District People′s Hospital of Chengdu in Sichuan Province,Chengdu,Sichuan,610300)

机构地区：[1]四川省成都市青白江区人民医院检验科,四川成都610300

出　　处：《实用临床医药杂志》2025年第2期69-74,共6页Journal of Clinical Medicine in Practice

基　　金：2023年成都市医学科研课题立项项目(2023497)。

摘　　要：目的探讨阿瑞匹坦(Apr)通过内质网应激(ERS)逆转结直肠癌(CRC)小鼠模型5-氟尿嘧啶(5-FU)耐药的分子机制。方法选取30只小鼠作为实验动物,随机分配其中5只为对照组(Control组),剩余25只采用背部皮下注射法构建HCT-116/5-FU CRC小鼠模型,并设为CRC组、5-FU组、Apr组、Apr+5-FU组和Apr+ERS抑制剂牛磺熊脱氧胆酸(TUDCA)组,每组5只。记录小鼠体质量变化及肿瘤发生情况,并计算其脏器指数。采用蛋白印迹法(WB)检测各组蛋白激酶R样内质网激酶(PERK)、真核翻译起始因子2亚基α(eIF2α)、激活转录因子4(ATF4)、C/EBP同源蛋白(CHOP)的蛋白表达水平。结果用药后5、10、15、20 d时,CRC组、5-FU组、Apr组、Apr+5-FU组、Apr+TUDCA组小鼠体质量的组间比较、时点比较及交互作用比较,差异无统计学意义(P>0.05)。末次给药2 d后,各组小鼠胸腺、肺脏、肝脏、脾脏、心脏、肾脏等脏器指数组间两两比较,差异无统计学意义(P>0.05)。与CRC组比较,Apr组、Apr+5-FU组小鼠PERK、p-eIF2α/eIF2α、ATF4、CHOP蛋白表达水平升高,肿瘤数量减少,肿瘤质量降低,肿瘤体积减小,差异有统计学意义(P<0.05),且Apr+5-FU组改善情况优于其他组,差异有统计学意义(P<0.05)。增加ERS抑制剂TUDCA干预后,抗肿瘤效应及ERS途径激活均受到抑制。结论Apr可增强CRC小鼠化疗敏感性并逆转其化疗耐药性,其可能通过介导ERS途径的下游分子发挥这一作用。Objective To investigate the molecular mechanism of aprepitant(Apr)reversing 5-Fluorouracil(5-FU)resistance in colorectal cancer(CRC)mouse model through endoplasmic reticulum stress(ERS).Methods Thirty mice were selected as experimental animals.Five mice were randomly assigned to control group,and the remaining 25 mice underwent subcutaneous injection in the back to establish the HCT-116/5-FU CRC mouse model.These mice were then divided into the CRC group,5-FU group,Apr group,Apr+5-FU group and Apr+ERS inhibitor Tauroursodeoxycholic acid(TUDCA)group,with five mice in each group.Changes in body weight and tumorigenesis in mice were recorded,and their organ indicators were calculated.Western blotting(WB)was used to detect the protein expression levels of protein kinase R-like ER kinase(PERK),eukaryotic initiation factor 2 subunitα(eIF2α),activating transcription factor 4(ATF4)and C/EBP homologous protein(CHOP)in each group.Results At 5,10,15 and 20 d after medication,there were no statistically significant differences in body weight among CRC,5-FU,Apr,Apr+5-FU and Apr+TUDCA groups,neither in time points nor in interactions(P>0.05).Two days after the last administration,there was no significant difference in the indexes of thymus,lung,liver,spleen,heart,kidney and other organs among all groups(P>0.05).Compared with CRC group,the protein expression levels of PERK,P-EIF2α/eIF2α,ATF4 and CHOP in Apr group and Apr+5-FU group were significantly increased,the number of tumors was significantly decreased,the tumor mass was significantly decreased,and the tumor volume was significantly decreased(P<0.05),and the improvement of Apr+5-FU group was better than that of other groups(P<0.05).Conclusion Apr can enhance chemotherapy sensitivity and reverse chemotherapy resistance in CRC mice,which may be mediated by downstream molecules of ERS pathway.

关 键 词：结直肠癌 阿瑞匹坦 内质网应激 5-氟尿嘧耐药 化疗敏感性 

分 类 号：R915[医药卫生—微生物与生化药学] R735.3[医药卫生—药学] R446