Exploring the mechanism of baicalin combined with geniposide in the treatment of colorectal cancer based on network pharmacology
Objective To investigate the mechanism of action of baicalin combined with geniposide in the treatment of colorectal cancer through network pharmacology.Methods The targets of baicalin and geniposide were obtained from Swiss Target Prediction,Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and STITCH databases.The targets of colorectal cancer-related diseases were obtained from GeneCards,TTD,and DrugBank databases.The protein-protein interaction(PPI)network was constructed by mapping the targets,and gene ontology(GO)analysis and kyoto encyclopedia of genes and genomes(KEGG)analysis were performed using the DAVID platform.Subsequently,the core targets were compared with Gnen Expression Omnibus(GEO)chip data.The SW480 cells of colorectal cancer cell line were divided into control group,baicalin group,geniposide group,and baicalin combined with geniposide group,and the expression of core targets was detected by quantitative real-time reverse transcription PCR(qRT-PCR).Results A total of 27 targets of baicalin and 54 targets of geniposide were obtained from Swiss Target Prediction,TCMSP and STITCH databases.After merging and removing duplicates,a total of 77 drug combination targets were obtained.Using"colorectal cancer"as the keyword,19 related targets were retrieved from TTD database,173 targets from GeneCards database,and 42 targets from DrugBank;after integrating and removing duplicates,a total of 223 colorectal cancer-related targets were obtained.The PPI relationship network of drug targets and disease targets was mapped,and there were 17 nodes and 71 edges in the PPI network of baicalin combined with geniposide in the treatment of colorectal cancer,with an average degree value of 8.353.Tumor necrosis factor(TNF),vascular endothelial growth factor A(VEGFA),interleukin-6(IL-6),v-myc avian myelocytomatosis viral oncogene homolog(MYC),caspase 3(CASP3),matrix metalloproteinase 2(MMP2),epidermal growth factor receptor(EGFR),human RAS proto-oncogene family member HRAS,Toll-like receptor 4(TLR4),prostaglandin-endoperoxide synthetase 2(PTGS2),TLR2 were the core nodes with an average degree value greater than that of other nodes.GO analysis and KEGG analysis were performed onthe targets of baicalin combined with geniposide in the treatment of colorectal cancer using the DAVID platform.GO analysis was mainlyrelated to protein binding,identical protein binding,enzyme binding,protein homodimer activity,protein heterodimer activity,etc.in terms of molecular function;it was also related to cytoplasm,plasma membrane,integral component of plasma membrane,membrane,cell surface,etc.in terms of cell component;it was also related to positive regulation of transcription from RNA polymerase II promoter,positive regulation of gene expression,negative regulation of apoptotic process,positive regulation of ERK1 and ERK2 cascade,response to drugs,etc.in terms of biological process;KEGG pathway enrichment analysis was highly related to phosphatidylinositol 3-kinase-protein kinase B signaling pathway(PI3K-Akt),mitogen-activated protein kinase(MAPK),hypoxia inducible factor-1(HIF-1)and other cancer-related pathways.Chip data showed that HRAS,TLR4,TNF were significantly different and might be the targets of baicalin combined with geniposide to directly fight against cancer.The qRT-PCR results showed that the mRNA expression levels of SW480 cells of colorectal cancer cell line were changed after treatment with baicalin and geniposide.The mRNA expression levels of HRAS in geniposide group and baicalin combined with geniposide group were(0.73±0.11)and(0.60±0.06),respectively,which were lower than that in control group(1.00±0.02),and the differences were statistically significant(all P＜0.05);the mRNA expression levels of TLR4 in baicalin group and baicalin combined with geniposide group were(0.71±0.11)and(0.66±0.04),respectively,which were lower than that in control group(1.00±0.03),and the differences were statistically significant(all P＜0.05);the mRNA expression levels of TNF-α in geniposide group and baicalin combined with geniposide group were(1.34±0.12)and(1.66±0.18),respectively,which were higher than that in control group(1.00±0.02),and the differences were statistically significant(all P＜0.05).Conclusions The action targets of baicalin combined with geniposide in the treatment of colorectal cancer at the molecular level.The combined action of baicalin and geniposide might target on HRAS,TLR4 and TNF-α,providing a theoretical basis for further development of this combination treatment.
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