双mTORC1/2抑制剂AZD2014可抑制裸鼠体内的人肝细胞癌的生长  

Antitumor effects of AZD2014,a dual mTORC1/2 inhibitor,against human hepatocellular carcinoma xenograft in nude mice

作　　者：廖晖 王毅 徐小平[1] 周陈杰[1] 张健民[1] 钟克波 杨定华[2] LIAO Hui;WANG Yi;XU Xiaoping;ZHOU Chenjie;ZHANG Jianmin;ZHONG Kebo;YANG Dinghua(Second Department of Hepatobiliary Surgery,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;Department of Hepatobiliary Surgery,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]南方医科大学珠江医院肝胆二科,广东广州510280 [2]南方医科大学南方医院肝胆外科,广东广州510515

出　　处：《南方医科大学学报》2021年第7期1056-1061,共6页Journal of Southern Medical University

基　　金：广东省自然科学基金(2018A030313214)。

摘　　要：目的体内研究双mTORC1/2抑制剂AZD2014对肝细胞癌是否具有抗癌作用。方法将肝癌细胞HCCLM3接种至祼鼠皮下,待形成明显瘤块,随机分成2组(对照组和AZD2014组),每组各5只。AZD2014组腹腔内注射AZD2014,5 mg/kg体质量,1次/d;对照组腹腔内注射药物溶剂2.5 mL/kg体质量,1次/d。定期测量肿瘤大小,绘制肿瘤体积增长曲线。给药后第24天,剥离皮下肿瘤,测量肿瘤的体积,并行HE染色和免疫组织化学检测细胞增殖、凋亡和EMT相关蛋白。结果AZD2014组肿瘤的体积自给药后几乎未再增大,而对照组中的肿瘤体积随着时间的延长而不断增大(P<0.001)。HE染色显示AZD2014组中发生坏死的细胞显著多于对照组。免疫组化检测发现AZD2014组中细胞增殖核抗原Ki-67和血管内皮细胞标志蛋白CD31的表达量显著低于对照组,而促凋亡蛋白Cleaved caspase-3显著高于对照组;此外,AZD2014组间质细胞表型蛋白N-cadherin和Vimentin的表达水平显著低于对照组,而上皮细胞表型蛋白E-cadherin的表达水平则显著高于对照组。结论AZD2014可以抑制肝细胞癌的增殖、微血管形成和EMT进程,同时还可以促进肝癌细胞发生坏死和凋亡。Objective To investigate the antitumor effects of AZD2014(a dual mTORC1/2 inhibitor)against human hepatocellular carcinoma(HCC)xenograft in mice.Methods HCCLM3 cells were injected subcutaneously in the right flank of nude mice,and when the tumors were macroscopic,the mice were randomized into 2 groups for daily intraperitoneal injection of AZD2014(5 mg/kg,n=5)or vehicle(5 mL/kg,n=5)for 24 days.Tumor growth was assessed using calipers every 4 days and the tumor growth curve was drawn.After the final injection,the mice were euthanized and the tumors were dissected for measuring tumor weight and histopathological analysis with HE staining.Immunohistochemical staining was used to detect the expressions of Ki-67,cleaved caspase-3,CD31,and the epithelial-mesenchymal transition(EMT)-related proteins(Ecadherin,N-cadherin,and vimentin)in the tumor tissue.Results Daily treatment with AZD2014 significantly suppressed HCC growth as compared with the control group.HE staining showed significantly increased tumor necrosis in AZD2014-treated mice.AZD2014 treatment inhibited tumor cell proliferation,angiogenesis and EMT progression as shown by decreased expressions of Ki-67,CD31,N-cadherin,and vimentin and increased expression of E-cadherin in the tumor tissue,and significantly promoted tumor cell apoptosis as shown by an increased expression of cleaved caspase-3 in AZD2014-treated mice.Conclusions AZD2014 is a highly potent antitumor agent for HCC in nude mice bearing HCC xenografts.AZD2014 can effectively inhibit tumor proliferation,angiogenesis and EMT progression and induce tumor cell necrosis and apoptosis.

关 键 词：肝细胞癌 MTOR抑制剂 分子靶向治疗 AZD2014 

分 类 号：R735.7[医药卫生—肿瘤]