仑伐替尼联合氟伐他汀对小鼠肝癌移植瘤的抑制作用及其机制  

The inhibitory effect of lenvatinib plus fluvastatin on liver transplantation tumor in mice and corresponding mechanism

作　　者：雷艺 程旸 林鑫盛 孙朋辉 康帅 李成 李建聪 朱云[1] LEI Yi;CHENG Yang;LIN Xin-sheng;SUN Peng-hui;KANG Shuai;LI Cheng;LI Jian-cong;ZHU Yun(Liver Tumor Center,Dept of Infectious Diseases and Hepatology Unit,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;Digestive Dept,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou 510623,China;Nanfang PET Center,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]南方医科大学南方医院感染内科肝脏肿瘤中心,广东广州510515 [2]广州医科大学附属广州市妇女儿童医疗中心消化科,广东广州510623 [3]南方医科大学南方医院PET中心,广东广州510515

出　　处：《中国药理学通报》2022年第10期1511-1516,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82073174&81802339);广州市科技计划(No 202102020185,202102020069)。

摘　　要：目的探究仑伐替尼联合氟伐他汀对小鼠肝移植瘤的抑制作用及其可能机制。方法构建裸小鼠肝癌皮下移植瘤模型,分别给予氟伐他汀单药、仑伐替尼单药、氟伐他汀联合仑伐替尼和对照溶剂:计算肿瘤倍增时间,免疫组织化学法检测移植瘤组织增殖细胞核抗原(PCNA)的表达水平;TUNEL法检测细胞凋亡水平;实时定量PCR和免疫组织化学法检测TLR4的表达;Western blot法检测β-catenin表达。培养体外肝癌细胞进行Rescue实验,Western blot法检测TLR4及β-catenin表达。结果裸鼠移植瘤实验中,与单药组及对照组相比,联合用药组肿瘤体积最小,肿瘤倍增时间明显延长(P<0.05),PCNA的表达明显降低(P<0.05),细胞凋亡水平明显升高(P<0.05)。联合用药组肝癌组织TLR4的表达较仑伐替尼组明显降低(P<0.05),同时,β-catenin的表达较仑伐替尼组明显降低。体外细胞实验中,过表达TLR4可以逆转氟伐他汀联合仑伐替尼诱导的β-catenin的表达下降。结论与单药仑伐替尼相比,仑伐替尼联合氟伐他汀可明显抑制小鼠肝移植瘤的增殖、促进其凋亡。联合用药可抑制仑伐替尼引起的TRL4及β-catenin的表达升高。联合用药可能是通过抑制TLR4来抑制β-catenin的表达。Aim To explore the inhibitory effect of lenvatinib plus fluvastatin on liver transplantation tumor in mice and the mechanism.Methods Mouse model of subcutaneous liver cancer was used.Single agent of lenvatinib,single agent of fluvastatin,a combination of lenvatinib and fluvastatin and control solvent were given to four groups of mice.Tumor volume was measured.Immunohistochemistry was used to examine proliferation of tumor cells.Tunel was employed to detect the cell apoptosis.qRT-PCR and immunohistochemistry were used to measure the expression of TLR4.Western blot was employed to determineβ-catenin expression.Rescue experiment was done using human hepatoma cells cultured in vitro.Results Treatment with both lenvatinib and fluvastatin significantly suppressed tumor growth in nude mice.Combined treatment significantly decreased the expressions of PNCA and increased apoptosis in tumor cells.Mechanically combined treatment synergistically suppressed the mRNA and protein expression of TLR4 which further inhibited the expression ofβ-catenin in hepatoma cells.Conclusions A combination of lenvatinib and fluvastatin synergistically inhibits tumor growth and promotes tumor cell apoptosis.The combination treatment significantly inhibits TLR4/β-catenin signaling pathway.

关 键 词：仑伐替尼 氟伐他汀 肝细胞癌 增殖 TOLL样受体4 Β-CATENIN 

分 类 号：R-332[医药卫生] R329.28R735.702.2R979.1