多纳非尼联合组蛋白去乙酰化酶抑制剂对肝癌细胞系的协同抗肿瘤作用  

Synergistic anti-tumor effect of donafenib combined with histone deacetylase inhibitor on hepatocarcinoma cell lines

作　　者：代雅风 李晖 吴迪 李晓婷[2] 张朋军 朱旭[1] DAI Ya-feng;LI Hui;WU Di;LI Xiao-ting;ZHANG Peng-jun;ZHU Xu(Department of Interventional Therapy,2 Department of Radiology,Peking University Cancer Hospital&Institute,Bejing 100142,China)

机构地区：[1]北京大学肿瘤医院暨北京市肿瘤防治研究所介入治疗科,北京100142 [2]北京大学肿瘤医院暨北京市肿瘤防治研究所影像科,北京100142

出　　处：《中国新药杂志》2024年第13期1370-1380,共11页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(82372054);登峰人才计划项目(DFL20220903)。

摘　　要：目的:探讨多纳非尼(donafenib)与组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)cambinol联合用药对肝细胞和肝癌细胞增殖和凋亡的影响以及对裸鼠体内人源肝癌移植瘤细胞(HuH-7)的治疗作用。方法:分别使用不同浓度的多纳非尼、cambinol单药及两药联合作用于HuH-7和Hep3B 2.1-7细胞系,采用CCK-8法检测吸光度以计算增殖抑制率;流式细胞术检测细胞凋亡与细胞周期;细胞划痕实验检测迁移能力;Western Blot法检测膜蛋白表达量;建立裸鼠皮下移植瘤模型以评估两药联合在体内是否存在协同抗肿瘤作用。结果:单独应用多纳非尼或cambinol均可抑制HuH-7和Hep3B 2.1-7细胞增殖,而联合用药组抑制增殖的能力显著增加(P<0.01),联合指数(combination index,CI)在两细胞系中均<1;联合用药组相较于单药组诱导细胞凋亡增加;处于各周期细胞的比例变化不明显;联合用药显著抑制肝癌细胞迁移和ATP结合盒转运体超家族成员三磷酸腺苷结合转运蛋白B1(ATP-binding cassette sub-family B member 1,ABCB1)蛋白表达;在体内实验中,联合用药协同抑制裸鼠移植瘤生长,Q值>1.15。结论:多纳非尼和cambinol联合用药可以较好地抑制肝癌细胞系增殖并且协同抑制裸鼠移植瘤生长,其机制与诱导细胞凋亡和抑制ATP结合盒转运体超家族成员ABCB1有关。Objective:To investigate the effect of donafenib combined with histone deacetylase inhibitor(HDACi)cambinol on the proliferation and apoptosis of hepatocellular carcinoma cells and the therapeutic efficacy of the combination on HuH-7 cell line xenografts in BALB/c-nude mice.Methods:HuH-7 and Hep3B 2.1-7 cell lines were treated with different concentrations of donafenib,cambinol and the combination of the two drugs.CCK-8 reagent was used to detect the OD value and then calculate the proliferation inhibition rate.Apoptosis and cell cycle were detected by flow cytometry.A xenograft model in BALB/c-nude mice was established to evaluate whether a synergistic effect exists for the combination of donafenib and cambinol in vivo experiments.Results:The proliferation of HuH-7 and Hep3B 2.1-7 cells was inhibited by donafenib or cambinol alone,and the ability to inhibit proliferation was significantly increased in the combination group(P<0.01).The combination index(CI)was less than 1 in both cell lines.Compared with the single drug groups,the combined drug group induced increased apoptosis.The proportion of cells in each cycle did not change significantly.The combination therapy group significantly inhibited the migration of liver cancer cells,and reduced the expression of ABCB1.Furthermore,the combined drug group synergistically suppressed the growth of xenograft tumors in BALB/c-nude mice with a Q value<1.15.Conclusion:The combination of donafenib and cambinol can inhibit the proliferation of tumor cells and synergistically suppress the growth of xenograft tumors in nude mice,which may be caused by the induction of apoptosis or related to ABCB1/MDR1/P-gp of the ATP binding cassette transporter superfamily.

关 键 词：多纳非尼 组蛋白去乙酰化酶抑制剂 肝癌细胞系 联合用药 协同作用 

分 类 号：R979.1[医药卫生—药品]