基于PTEN/PI3K/AKT信号通路探讨旋覆花汤联合索拉非尼对肝癌荷瘤小鼠的抗肿瘤作用  

The anti-tumor effect of Xuanfuhua decoction combined with sorafenib on liver cancer bearing mice based on PTEN/PI3K/AKT signaling pathway

作　　者：苏茜茜 韩亮 罗文昭 赵长普 SU Qian-qian;HAN Liang;LUO Wen-zhao;ZHAO Chang-pu(Dept of Hepatobiliary,Spleen and Stomach;Dept of Oncology,Henan Provincial Hospital of Traditional Chinese Medicine(the Second Affiliated Hospital of Henan University of Chinese Medicine),Zhengzhou 450053,China)

机构地区：[1]河南省中医院,河南中医药大学第二附属医院肝胆脾胃科,河南郑州450053 [2]河南省中医院,河南中医药大学第二附属医院肿瘤科,河南郑州450053

出　　处：《中国药理学通报》2024年第10期1884-1892,共9页Chinese Pharmacological Bulletin

基　　金：河南省重点研发与推广专项(科技攻关)支持项目(No 222102310108);河南省中医药科学研究专项课题(No 20-21ZY2124);河南省中医药青苗人才培养项目(No豫卫中医函[2021]16号)。

摘　　要：目的探讨旋覆花汤联合索拉非尼对肝癌荷瘤小鼠的影响及机制。方法KM小鼠分为肝癌组、旋覆花汤组、索拉非尼组、联合组、联合+PTEN抑制剂(BPV)组、联合+PI3K激活剂(IGF-1)组、空白组。液相色谱-质谱检测肝癌组和旋覆花汤组小鼠血清旋覆花汤入血成分;检测血清ALT、AST及瘤重、瘤体积变化;检测肿瘤组织病理、TUNEL、p53、Bax阳性细胞数占比、IFN-γ、TNF-α水平及PTEN、p-PI3K、p-AKT蛋白变化。体外实验观察联合处理对小鼠肝癌H22细胞增殖、凋亡的影响。结果旋覆花汤入血成分11种。与肝癌组相比,旋覆花汤组、索拉非尼组、联合组肿瘤细胞分散,血清AST、ALT水平、瘤重、瘤体积及p-PI3K、p-AKT蛋白降低,肿瘤组织中TUNEL、p53、Bax阳性细胞数占比、IFN-γ、TNF-α水平及PTEN蛋白升高,且联合组趋势最明显(P<0.05);BPV或IGF-1逆转了联合处理对肝癌荷瘤小鼠的抗肿瘤作用。体外实验发现,联合处理对H22细胞增殖的抑制及细胞凋亡的促进作用优于旋覆花汤或索拉非尼单独处理;BPV或IGF-1逆转了联合处理对H22细胞增殖、凋亡的作用。结论旋覆花汤联合索拉非尼可能通过上调PTEN抑制PI3K/AKT通路发挥对肝癌荷瘤小鼠的抗肿瘤作用。Aim To investigate the effect of Xuanfuhua decoction combined with sorafenib on liver cancer bearing mice and the underlying mechanism.Methods KM mice were divided into the liver cancer group,Xuanfuhua decoction group,sorafenib group,combination group,combination+PTEN inhibitor(BPV)group,combination+PI3K activator(IGF-1)group and blank group.Liquid chromatography-mass spectrometry was used to detect the blood components of Xuanfuhua decoction in serum of mice in liver cancer group and Xuanfuhua decoction group.The changes of serum ALT,AST,tumor weight and tumor volume were detected.The pathological changes of tumor tissue,the proportion of TUNEL,p53 and Bax positive cells,the levels of IFN-γand TNF-α,and the protein changes of PTEN,p-PI3K and p-AKT were detected.The effects of combined treatment on the proliferation and apoptosis of H22 cells of mouse hepatoma were observed in vitro.Results There were 11 constituents absorbed into blood of Xuanfuhua decoction.Compared with the liver cancer group,the tumor cells in the Xuanfuhua decoction group,sorafenib group,and combination group were dispersed,the serum AST and ALT levels,tumor weight,tumor volume,and p-PI3K and p-AKT proteins decreased,the proportion of TUNEL,p53 and Bax positive cells,IFN-γ,TNF-αlevels,and PTEN protein in tumor tissue increased,and the trend of the combination group was the most obvious(P<0.05).BPV or IGF-1 reversed the anti-tumor effect of the combined treatment on liver cancer bearing mice.In vitro experiments showed that the combined treatment could inhibit the proliferation of H22 cells and promote the apoptosis of H22 cells better than Xuanfuhua decoction or sorafenib alone.BPV or IGF-1 reversed the effects of combined treatment on the proliferation and apoptosis of H22 cells.Conclusion Xuanfuhua decoction combined with sorafenib may exert anti-tumor effect on liver cancer bearing mice by up-regulating PTEN and inhibiting PI3K/AKT pathway.

关 键 词：旋覆花汤 索拉非尼 肝癌 凋亡 张力蛋白同源物/磷脂酰肌醇3-激酶/蛋白激酶B通路 增殖 

分 类 号：R-332[医药卫生] R289.5R329.25R345.57R735.7R979.1