芪玉三龙方通过CBS/GPX4调控铁死亡促进肺癌移植瘤小鼠对顺铂的敏感性  

Promotion of Qiyu Sanlong Decoction on the sensitivity of subcutaneous tumor model of lung cancer to cisplatin by promoting ferroptosis via CBS/GPX4

作　　者：刘桐 张波克 张星星[2] 高雅婷 童佳兵[1,2,3] 李泽庚 LIU Tong;ZHANG Boke;ZHANG Xingxing;GAO Yating;TONG Jjabing;LI Zegeng(Anhui University of Chinese Medicine,Hefei 230038,China;The First Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230031,China;Anhui Province Key Laboratory of the Application and Transformation of Traditional Chinese Medicine in the Prevention and Treatment of Major Pulmonary Diseases,Hefei 230031,China)

机构地区：[1]安徽中医药大学,合肥230038 [2]安徽中医药大学第一附属医院,合肥230031 [3]安徽省重点实验室中医药防治肺系重大疾病应用转化,合肥230031

出　　处：《中华中医药杂志》2024年第5期2343-2348,共6页China Journal of Traditional Chinese Medicine and Pharmacy

基　　金：国家自然科学基金面上项目(No.81874431);安徽省自然科学基金面上项目(No.2308085MH291);安徽省教育厅自然科学研究重点项目(No.KJ2021A0542,No.KJ2020A0417);安徽省临床医学研究转化专项(No.202304295107020111)。

摘　　要：目的:基于生物信息技术和动物实验,探究芪玉三龙方提高肺癌顺铂敏感性的潜在作用机制。方法:分析转录组数据得到肺癌和顺铂耐药的差异基因,采用人工智能策略预测芪玉三龙方的靶蛋白,对取交集获得的潜在作用靶点进行GO生物过程及KEGG通路富集分析,随后进行基因依赖分析和分子对接,确定关键标志物,最后构建肺癌A549/DDP皮下瘤模型进行验证。结果:获得芪玉三龙方与肺癌顺铂耐药相关的潜在有效靶点186个,富集的生物学过程有细胞对过氧化氢的反应、细胞氧化解毒;功能通路有谷胱甘肽代谢、铂类药物的耐药性等。基因依赖分析鉴定出与铁死亡相关的基因CBS为核心的靶点,分子对接显示CBS与芪玉三龙方的核心活性成分有良好的亲和力,与贝母辛的结合亲和力最高。动物实验结果显示芪玉三龙方联合顺铂组肿瘤组织可见大片状坏死的细胞。与顺铂组比较,联合组能够上调4HNE和TFR蛋白的表达,下调CBS和GPX4蛋白的表达。结论:芪玉三龙方能够提高肺癌的顺铂耐药肿瘤组织对于顺铂的敏感性,其作用机制可能与抑制铁死亡关键分子CBS、GPX4表达有关。Objective:To investigate the potential mechanism of Qiyu Sanlong Decoction in the enhancement of cisplatin sensitivity in lung cancer based on Bioinformatics and animal experiments.Methods:TCGA database was analyzed to obtain differential genes for lung cancer and cisplatin resistance.The artificial intelligence strategy was used to predict the targets of Qiyu Sanlong Decoction.The intersection was constructed and the core targets were screened for GO and KEGG enrichment analysis.Gene Dependence analysis and Molecular docking was performed for core target,and finally A549/DDP cells were used to construct the subcutaneous tumor model of lung cancer for validation.Results:Qiyu Sanlong Decoction had 186 potential effective targets associated with cisplatin resistance in lung cancer.The main biological processes included cellular response to hydrogen peroxide,and cellular oxidant detoxification,and the main functional pathways included glutathione metabolism,and platinum drug resistance.Genetic dependency analysis identified CBS as a core target associated with ferroptosis.Molecular docking showed that CBS had good affinity for the core active ingredients of Qiyu Sanlong Decoction,with the best binding affinity for peimisine.The animal experiments results showed that Qiyu Sanlong Decoction combined with cisplatin could result in large sheets of necrotic cells in the tumor tissues.Compared with the cisplatin group,the combination group was able to upregulate the expression of 4HNE and TFR proteins,and down-regulate the expression of CBS and GPX4 proteins compared with the cisplatin group.Conclusion:Qiyu Sanlong Decoction was able to increase the sensitivity of cisplatin-resistant tumor tissues to cisplatin,and its mechanism may be through inhibiting ferroptosis-related proteins CBS and GPX4 to play a role.

关 键 词：芪玉三龙方 肺癌 A549/DDP细胞 铁死亡 CBS 

分 类 号：R285.5[医药卫生—中药学]