南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (5): 649-657.doi: 10.12122/j.issn.1673-4254.2022.05.04

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黄芪四君子汤治疗乳腺癌癌因性疲乏的疗效及机制：基于94例临床随机对照试验和网络药理学

崔艺馨，米继伟，冯 宇，李灵生，王雨佳，呼 健，王海明   

  1. 中国人民解放军总医院中医医学部，北京 100853；湛江中心人民医院全科医学科，广东 湛江 524045
  • 出版日期:2022-05-20 发布日期:2022-06-02

Huangqi Sijunzi decoction for treating cancer-related fatigue in breast cancer patients: a randomized trial and network pharmacology study

CUI Yixin, MI Jiwei, FENG Yu, LI Lingsheng, WANG Yujia, HU Jian, WANG Haiming   

  1. Department of Traditional Chinese Medicine, General Hospital of Chinese PLA, Beijing 100853, China; Department of General Practice, Zhanjiang Central People's Hospital, Zhanjiang 524045, China
  • Online:2022-05-20 Published:2022-06-02

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摘要： 目的 探讨黄芪四君子汤治疗乳腺癌化疗后致脾胃气虚型癌因性疲乏（CRF）患者的临床疗效及作用机制。方法 94例脾胃气虚型癌因性疲乏的乳腺癌化疗患者随机分为化疗组47例和中药+化疗组47例。化疗组常规行多柔比星+环磷酰胺或表柔比星+环磷酰胺（AC/EC）方案化疗及心理疏导等非药物性干预，中药+化疗组是在化疗组基础上加用黄芪四君子汤口服治疗，21 d 为1个疗程，观察服药1个疗程后疲乏情况（Piper疲乏修订量）。依托中药系统药理学分析平台（TCMSP）、GeneCards、NCBI基因以及OMIM数据库检索得到黄芪四君子汤的活性成分和靶点蛋白以及CRF、乳腺癌相关疾病靶点，构建蛋白互作（PPI）网络，并对靶标进行基因本体（GO）功能富集分析、京都基因与基因组百科全书（KEGG）通路富集分析，运用AutoDock软件预测主要药物化合物与CRF关键靶点的结合度。结果 中药+化疗组对CRF患者的躯体疲乏、情感疲乏、认知疲乏3个维度评分及疲乏总评分情况明显好于化疗组（P<0.001）；本研究共筛得黄芪四君汤250个靶标、癌因疲乏相关基因2653个、乳腺癌相关基因15 329个，方药与疾病交集靶标161个，构建PPI网络，拓扑分析筛得最可能的关键靶点66个，GO及KEGG富集分析预测出与疾病相关的多条作用通路；分子对接研究提示黄芪四君子汤的核心成分均与AKT1、CASP3、IL6、JUN、VEGFA关键靶点有较好的亲和力， 且AKT1可能是黄芪四君子汤治疗癌因性疲乏的最重要核心靶点。结论 黄芪四君子汤可明显改善乳腺癌癌因性疲乏，其作用机制可能主要通过AKT1调控 PI3K-Akt等信号通路相关基因的表达，进而发挥抗CRF的药理效应。

关键词: 黄芪四君子汤；癌因性疲乏；网络药理学；分子对接；乳腺癌化疗

Abstract: Objective To evaluate the clinical efficacy of Huangqi Sijunzi decoction (HQSJZD) for treating cancer-related fatigue (CRF) of spleen and stomach Qi deficiency type after chemotherapy in patients with breast cancer. Methods A total of 94 breast cancer patients who developed CRF of spleen and stomach Qi deficiency type after chemotherapy were randomized into chemotherapy group (n=47) and traditional Chinese medicine (TCM) + chemotherapy group (n=47). The patients in chemotherapy group received the AC or EC regimen and non-drug interventions including psychological counseling, and those in TCM + chemotherapy group received oral administration of HQSJZD in addition to chemotherapy for 21 days as a treatment cycle, after which improvement of fatigue was assessed using Modified Piper Fatigue Scale. The active ingredients and targets of HQSJZD were screened using the TCM System Pharmacology Analysis Platform (TCMSP); the CRF- and breast cancer-related disease targets were retrieved based on data from the GeneCards, NCBI gene and OMIM databases to construct the component-target network and the protein-protein interaction (PPI) network. GO functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes KEGG pathway enrichment analysis of the target genes were performed to construct the component-disease-pathway- target biological network. The binding strength of the major drug ingredients and CRF key targets were predicted using AutoDock software. Results The scores for somatic fatigue, emotional fatigue and cognitive fatigue, along with the overall fatigue score, showed more significant improvements in TCM+chemotherapy group than in chemotherapy group (P<0.001), and the response rate reached 89.4% in the combined treatment group. We identified 250 targets for HQSJZD, 2653 CRF-related genes, 15 329 breast cancer-related genes and 161 prescription-disease intersected targets, from which topological analysis identified 66 potential key targets. GO and KEGG enrichment analyses predicted multiple pathways related with the disease. Molecular docking results suggested that the core ingredients of HQSJZD showed high affinities to the key targets AKT1, CASP3, IL6, JUN and VEGFA, among which AKT1 might be the most important target for HQSJZD to treat CRF. Conclusion HQSJZD can obviously improve CRF symptoms in breast cancer patients possibly by regulating multiple signaling pathways including PI3K-Akt through AKT1.

Key words: Huangqi Sijunzi decoction; cancer-related fatigue; network pharmacology; molecular docking; breast cancer chemotherapy