基于网络药理学研究重楼皂苷抗肿瘤的协同机制

Synergistic Mechanism of Polyphyllins against Tumor Based on Network Pharmacology

为系统探究重楼皂苷抗肿瘤的协同机制,基于重楼皂苷的含量和活性筛选其抗肿瘤成分,利用靶点数据库获取入选皂苷成分的抗肿瘤靶点,并借助蛋白互作网络分析选出重楼皂苷抗肿瘤的主要作用靶点,对主要作用靶点进行GO(gene ontology)生物过程富集、KEGG(kyoto encyclopedia of genes and genomes)通路富集,使用Origin 2019b软件构建重楼抗肿瘤的主要皂苷成分-主要作用靶点-主要通路关联网络,分析该网络节点的拓扑参数,进一步明确重楼皂苷抗肿瘤的分子机制。结果显示重楼皂苷Ⅰ、重楼皂苷Ⅱ、重楼皂苷Ⅵ、重楼皂苷Ⅶ、重楼皂苷H、薯蓣皂苷及纤细薯蓣皂苷7个主要皂苷成分作用于38个抗肿瘤主要作用靶点,包括转录与凋亡相关的TP53、AKT1、MYC、CASP3、JUN、MAPK3、ERBB2、STAT3、SRC、MAPK8、BCL2L1、CTNNB1、MAPK1、CREB1、FOXO1、CASP8、FOS;炎症相关的IL6、TNF、IL1B、PTGS2、IL2;血管生成相关的EGFR、VEGFA、EGF、FGF2。参与DNA转录、细胞增殖及凋亡、RNA聚合酶Ⅱ启动子转录、一氧化氮生物合成、磷脂酰肌醇3-激酶信号转导等生物过程;调控卡波济肉瘤相关疱疹病毒(HHV-8)、人巨细胞病毒(HCMV)、人乳头瘤病毒(HPV),乳腺癌、大肠癌、前列腺癌以及PI3K-Akt、TNF、MAPK、mTOR、p53等通路。由此可见,重楼皂苷主要通过促凋亡、抗炎、抗病毒、抗血管生成,以及影响肿瘤细胞信号转导等多种机制,协同产生抗肿瘤效应。

The synergistic mechanism of Polyphyllins against tumor was studied.Main antitumor Polyphyllins were screened out based on their content and activity.The antitumor targets of included components were obtained from target databases,and these targets were used for protein-protein interaction(PPI)analysis.The main targets derived from PPI analysis were used for GO(gene ontology)biological processes enrichment,and KEGG(kyoto encyclopedia of genes and genomes)signaling pathways enrichment.Finally,Origin 2019b was used to construct an associated network of main saponins-main targets-main signaling pathways,and the topology parameters of the network nodes were analyzed to further clarify its antitumor molecular mechanism.The results show that a total of 7 Polyphyllins including polyphyllinⅠ,polyphyllinⅡ,polyphyllinⅥ,polyphyllinⅦ,polyphyllin H,dioscin,and gracillin are screened out,which act on 38 antitumor main targets.These targets include transcription and apoptosis relating TP53,AKT1,MYC,CASP3,JUN,MAPK3,ERBB2,STAT3,SRC,MAPK8,BCL2L1,CTNNB1,MAPK1,CREB1,FOXO1,CASP8,FOS;inflammatory response relating IL6,TNF,IL1B,PTGS2,IL2;angiogenesis-relating EGFR,VEGFA,EGF,and FGF2.The 38 targets participate in DNA transcription,cell proliferation and apoptosis,RNA polymerase II promoter transcription,nitric oxide biosynthesis,and phosphatidylinositol 3-kinase signal transduction relevant biological processes;regulate pathways such as Kaposi s Sarcoma-related herpes virus(HHV-8),human cytomegalovirus(HCMV),human papillomavirus(HPV),breast cancer,colorectal cancer,prostate cancer,PI3K-Akt,TNF,MAPK,mTOR,and p53.It is concluded that Polyphyllins have synergistic anti-tumor mechanism by promoting apoptosis,anti-inflammation,anti-virus,anti-angiogenesis,and influencing tumor cells signaling transduction.