复方胃痛胶囊靶向磷酸化AKT1抑制前列腺癌生长  

A Compound Stomachache Capsules Against Prostate Cancer by Targeting Phosphorylated AKT1

作　　者：余佳 宋玉 万小青 程莎 徐应江 骆衡 YU Jia;SONG Yu;WAN Xiao-Qing;CHENG Sha;XU Ying-Jiang;LUO Heng(Natural Products Research Center of Guizhou Province,Guiyang 550014,China;State Key Laboratory of Function and Applications of Medical Plants,Guizhou Medical University,Guiyang 550014,China;Wansheng Pharmaceutical CO.LTD,Zunyi 564401,Guizhou,China)

机构地区：[1]贵州省天然产物研究中心,贵阳550014 [2]贵州医科大学省部共建药用植物与功效国家重点实验室,贵阳550014 [3]贵州万胜药业有限责任公司,贵州遵义564401

出　　处：《中国生物化学与分子生物学报》2023年第11期1606-1619,共14页Chinese Journal of Biochemistry and Molecular Biology

基　　金：贵州省自然科学基金资助项目(黔科合支撑[2021]一般412,黔科合基础-ZK[2022]重点031;黔科合支撑[2022]一般194);贵州省“百层次”人才项目(黔科合平台人才-GCC[2022]034-1)资助。

摘　　要：靶向AKT1抗癌药物的研发在多种癌症中被报道,但中药复方靶向AKT1的相关研究较少。本研究探讨了一种治疗胃病中药配方——复方胃痛胶囊,通过靶向AKT1在体内外发挥抗前列腺癌生长的作用。通过质谱、靶点预测及生物信息学分析发现,复方胃痛胶囊主要成分中有37种化合物成分具有抗癌活性,木兰花碱[(+)-Magnoflorine]、7-羟基香豆素(7-hydroxycoumarin)等6种成分可能是其抗前列腺癌的主要活性成分。MTT、ROS、细胞凋亡及细胞周期结果显示,复方胃痛胶囊对前列腺癌细胞具有显著的体外抑制作用(P<0.01),80μg/mL浓度下PC3细胞生长抑制率达35%左右,上调ROS产生,并显著促进细胞凋亡(P<0.01)及G 2/M期阻滞(P<0.01)。体内研究结果证实,该药物对皮下前列腺癌肿瘤形成有显著抑制作用(P<0.01)。PPI网络互作、生物信息学分析显示,AKT1、CCND1、ERS1、EGFR等靶点可能发挥核心作用。分子对接及细胞热稳定性结果证实,磷酸化的AKT是复方胃痛胶囊的作用靶点之一(P<0.01),且复方胃痛胶囊显著抑制pAKT(Ser473)表达。本研究证实,复方胃痛胶囊能在体内外抗前列腺癌生长,且可能通过靶向抑制pAKT(Ser473)发挥作用,并探讨了中药复方靶向AKT1治疗前列腺癌的可能性。The development of anticancer drugs targeting AKT1 has been reported in a variety of cancers,but there are few related studies on Chinese medicinals targeting AKT1.In this study,Compound stomachache capsules(CSC)was used for inhibiting prostate cancer(PC)cells growth by targeting AKT1 in vitro and in vivo.Through mass spectrum,target prediction and bioinformatics analysis,it is found that 37 of CSC compounds have anticancer activity,and 6 compounds such as(+)-Magnoflorine,7-hydroxycoumarin may be their main active components against prostate cancer.The results showed that CSC had significant in vitro inhibition on the growth of prostate cancer cells(P<0.01),and the growth inhibition rate of PC3 cells reached about 35%at 80μg/mL.CSC also increased ROS production,and significantly promoted apoptosis(P<0.01)and G 2/M phase arresting(P<0.01).Besides,the in vivo results confirmed that the drug had significant inhibitory effects on subcutaneous prostate cancer tumor formation(P<0.01).Furthermore,Protein-Protein Interaction networks(PPI)and bioinformatics analysis revealed that AKT1,CCND1,ERS1,and EGFR may play a central role.Molecular docking and cellular thermal shift assay confirmed that pAKT(Ser473)is one of the targets of CSC(P<0.01),and significantlyinhibited pAKT(Ser473)expression.This study confirmed that the CSC against prostate cancer cells growth in vitro and in vivo by targeting pAKT(Ser473),and explored the possibility of TCM compound targeted pAKT(Ser473)for the treatment of prostate cancer.

关 键 词：中药 pAKT(Ser473) 复方胃痛胶囊 前列腺癌 

分 类 号：Q279[生物学—细胞生物学] Q966