白藜芦醇通过EGFR/AKT/mTOR通路改善结直肠癌细胞伊立替康化疗耐药性  

Resveratrol ameliorates irinotecan chemoresistance of colorectal cancer cells by down-regulating EGFR/AKT/mTOR signaling pathway

作　　者：王丽[1] 庞静[2] 沈慧 寇茜睿 王玉珏 张静[1] 李芳 WANG Li;PANG Jing;SHEN Hui;KOU Qian-rui;WANG Yu-jue;ZHANG Jing;LI Fang(School of Basic Medicine,Medical School of Yan′an University,Affiliated Hospital of Yan′an University,Yan′an Shaanxi 716000,China;Dept of Endocrinology and Metabolism,Affiliated Hospital of Yan′an University,Yan′an Shaanxi 716000,China)

机构地区：[1]延安大学医学院基础医学院,陕西延安716000 [2]延安大学附属医院内分泌代谢科,陕西延安716000

出　　处：《中国药理学通报》2023年第12期2280-2287,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82260530);陕西省自然科学基础研究计划项目(No 2022JQ-907);陕西省高校科协青年人才托举计划项目(No 20210309)。

摘　　要：目的探讨白藜芦醇(resveratrol,RES)联合伊立替康(irinotecan,IRI)治疗结直肠癌(colorectal cancer,CRC)的可能性及RES改善CRC细胞IRI化疗耐药性的相关分子机制。方法以CRC细胞HT-29和RKO为研究对象,通过MTT和克隆形成实验检测分析RES、IRI及两者联合对CRC细胞增殖能力的影响;划痕实验检测分析RES、IRI及两者联合对CRC细胞迁移能力的影响。在此基础上探究分析RES在CRC细胞IRI化疗耐药性调控中的作用及相关分子机制。结果RES与IRI联合处理组CRC细胞的增殖和迁移能力均明显低于IRI单药处理组细胞,即RES可明显增强IRI对CRC细胞增殖和迁移的抑制作用,表明RES能够改善CRC细胞的IRI化疗耐药性。相比于IRI单药处理组,RES与IRI联合处理组CRC细胞中EGFR/AKT/mTOR信号通路标志蛋白的表达水平均明显下调。而EGFR激活剂(NSC 228155)与AKT激活剂(SC79)均可逆转RES对CRC细胞IRI化疗耐药性的改善作用,反之,AKT抑制剂(MK2206)能够部分逆转NSC 228155的这种作用。结论RES可通过下调EGFR/AKT/mTOR信号通路来抑制CRC细胞增殖和迁移,进而改善CRC细胞IRI化疗耐药性,提示RES联合IRI可作为CRC临床治疗的一种可能方案。Aim To explore the possibility of resveratrol(RES)combined with irinotecan(IRI)in the treatment of colorectal cancer(CRC)and the underlying molecular mechanism of RES ameliorating IRI chemoresistance of CRC cells.Methods CRC cells used in this study were HT-29 and RKO cells.The effects of RES,IRI and their combination on the proliferation of CRC cells were analyzed by MTT assay and colony formation assay.The effects of RES,IRI and their combination on the migration of CRC cells were assessed by Wound-healing assay.On this basis,the role of RES in regulating IRI chemoresistance of CRC cells and the underlying molecular mechanisms were further explored.Results The proliferation and migration ability of CRC cells in the RES and IRI combined treatment group were significantly lower than those in the IRI treated group,which showed that RES could enhance the inhibiting effect of IRI on the proliferation and migration of CRC cells,indicating that RES was able to ameliorate the chemoresistance of CRC cells to IRI.And remarkably lower marker proteins expression levels of EGFR/AKT/mTOR signaling pathway in the RES and IRI combined treatment group was observed.Moreover,both EGFR activator(NSC 228155)and AKT activator(SC79)could reverse the ameliorating effect of RES on IRI chemoresistance of CRC cells,whereas AKT inhibitor(MK2206)could partially reverse the effect of NSC 228155.Conclusions RES can inhibit the proliferation and migration of CRC cells by downregulating EGFR/AKT/mTOR signaling pathway,so as to ameliorate the chemoresistance of CRC cells to IRI,suggesting that RES combined with IRI can be a promising novel treatment for CRC.

关 键 词：结直肠癌 白藜芦醇 伊立替康 增殖 迁移 化疗耐药 

分 类 号：R284.1[医药卫生—中药学] R329.28[医药卫生—中医学] R735.35R979.1