阿司匹林抑制核因子-κB增强索拉非尼对肝癌的促凋亡作用  

Enhancement of apoptosis by aspirin combined with sorafenib in a highly metastatic murine model of human hepatocellular carcinoma

作　　者：张伟[1] 孙惠川[2] 熊宇泉[3] 庄鹏远[4] 朱小东[2] 汤钊猷[2] 

机构地区：[1]天津医科大学附属肿瘤医院研究所肝胆外科天津市肿瘤防治重点实验室,300060 [2]复旦大学肝癌研究所中山医院 [3]美国康奈尔大学医学院 [4]上海交通大学附属新华医院肝胆外科

出　　处：《中华实验外科杂志》2011年第10期1620-1622,共3页Chinese Journal of Experimental Surgery

基　　金：国家自然科学基金

摘　　要：目的观察合用阿司匹林（Aspirin）与索拉非尼（Sorafenib）对肝癌生长转移的抑制作用和促凋亡作用并探讨其机制。方法采用人肝癌裸鼠原位模型LCI-D20，分为对照组、Sorafenib单用组（30mg／kg灌胃，1d1次）、Sorafenib＋Aspirin合用组、Aspirin单用组（30mg／kg灌胃，1d1次），治疗4周后观察荷瘤小鼠生存期、肿瘤体积、肺转移，定量比较肿瘤细胞凋亡指数，观察各组荷瘤鼠生存期，检测各组核因子-κB（NF-κB）及IKBα表达。结果对照组、Sorafenib治疗组、Sorafenib＋Aspirin合用组、Aspirin治疗组肿瘤体积分别为（4．76±0．51）、（1．41-4-0．08）、（0．66±0．12）和（4．58±0．47）cm3；肺转移灶数目分别为（189±21）、（96±15）、（30±17）和（92±18）个；中位生存期分别为72、98、112、80d。肿瘤凋亡指数分别为（2．6±1．1）％、（8．6±3．7）％、（24．3±6．9）％和（6．8±1．5）％；与Sorafenib治疗组比较，Sorafenib＋Aspirin合用明显降低肿瘤体积（P〈0．05）、抑制肺转移灶数目（P〈0．01），延长荷瘤鼠生存期（P〈0．05）和促进肿瘤细胞凋亡（P〈0．05）。Sorafenib在肝癌中具有下调IKBcx和上调NF-κB—p65的作用而合用Aspirin可逆转此作用。结论Aspirin通过抑制NF．KB活化，进一步增强Sorafenib对肝癌凋亡的促进作用及对肝癌生长转移的抑制作用，并延长荷瘤鼠生存期。Objective To investigate the effect of combination of sorafenib and aspirin on tumor apoptosis, tumor growth, lung metastasis and survival of tumor-bearing nude mice in a highly metastatic xenograft murine model of human hepatocellular carcinoma （HCC） and explore the mechanism. Methods The Xenograft of a highly metastatic human HCC tumor （LCI-D20） was used to evaluate survival, primary tumor growth and lung metastasis after treatment with aspirin alone or in combination with sorafenib. Apoptosis of tumor cells in vivo was determined by the terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling assay （TUNEL）. Results Tumor volumes were （4. 76 ±0. 51 ）, （ 1.41 ±0. 08）, （0. 66 ±0. 12） and （4. 58 ±0.47） cm3 in control, sorafenib, sorafenib plus aspirin, and aspirin groups, respectively. Lung metastases were 189 ±21, 96 ± 15, 30 ± 17 and 92 ± 18 in four groups, and median survival was 72, 98, 112 and 80 days, respectively. Apoptosis rate was （2. 6 ± 1.1 ） % , （ 8.6 ± 3.7 ） % , （ 24. 3 ± 6. 9）% and （6. 8 ± 1.5 ）% respectively in four groups. Combination of aspirin and sorafenib significant- ly decreased tumor volume （ P 〈 0.05 ）, inhibited number of lung metastases （ P 〈 0. 01 ）, and prolonged survival （P 〈 0. 05 ） as compared with sorafenib alone group. Increased apoptosis of tumor ceils （P 〈0. 05 ） was observed by combination of aspirin and sorafenib. Nuclear factor-κB （NF-κB） was upregulated and IκBct was downregulated by sorafenib, which was reversed by combination of aspirin with sorafenib. Conclusion Aspirin significantly promoted apoptosis of tumor cells in combination with sorafenib through inhibiting sorafenib-induced NF-κB activation.

关 键 词：癌 肝细胞 索拉非尼 阿司匹林 核因子-ΚB 

分 类 号：R965[医药卫生—药理学]