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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 43-53

Network pharmacology-based study of the active constituents of Chinese medicinal formulae for antitumor mechanism


1 Institute of Materia Medica, Chinese Academy of Medical Sciences And Peking Union Medical College, Beijing 100050, China
2 School of Pharmaceutical Sciences, Wuhan University, Wuhan 430072, China
3 Institute of Materia Medica, Chinese Academy of Medical Sciences And Peking Union Medical College; Beijing Key Laboratory of Drug Target and Screening Research; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China

Date of Web Publication2-Jul-2018

Correspondence Address:
Ai-Lin Liu
Institute of Materia Medica, Chinese Academy of Medical Sciences and PekingUnionMedicalCollege,Beijing100050
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_6_18

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  Abstract 


Objective: To investigate the network pharmacology of anti-tumor Chinese medicinal formulae and explain the synergistic mechanism of various active ingredients of Chinese medicinal formulae. Methods: We collected the anti-tumor Chinese medicinal formulae and chose several single herbs with the top frequency for further study. The chemical constituents of these herbs were downloaded from databases CNPC and Traditional Chinese Medicine Systems Pharmacology and were analyzed to set up the anti-tumor material basis. The genes regulated by these constituents were retrieved in Traditional Chinese Medicine integrated database and Comparative Toxicogenomics database. Results: We collected 65 anti-tumor Chinese medicinal formulae, and 4 single herbs were selected, including Licorice, Radix astragali, Panax ginseng, and Radix scutellariae, which consist of 172, 70, 293, and 92 known constituents, respectively. The constituent–gene network, protein–protein interaction network, gene–pathway enrichment network, and gene–disease network were constructed. Moreover, molecular docking was employed to clarify the interactions between active constituents and key drug targets (PTG2, epidermal growth factor receptor, peroxisome proliferator-activated receptor gamma, estrogen receptor 1, mammalian target of rapamycin, AKT1, mitogen-activated protein kinase 1 [MAPK1], peroxisome proliferator-activated receptor alpha, and MAPK8). Most of the constituents could act on multiple targets, whose structures mainly belong to alkaloids, flavonoids, and their glycosides, organic acids, or dianthrone, and their representative chemical constituents include narcissus glycosides, rutin, dauricine, scutellarin, baicalin, isoschaftoside, and leucovorin. Conclusion: The network mechanism of the effective constituents from traditional Chinese medicines (TCMs) for anti-tumor therapy was partially uncovered by using statistical methods, network pharmacology methods, and molecular docking methods. This study will provide important information for new drug design with multiple targets for anti-tumor therapy.

Keywords: Data mining, molecular docking, network pharmacology, traditional Chinese medicine, tumor


How to cite this article:
Zhang BY, Zheng YF, Pang XC, Wang Z, Ding H, Liu AL. Network pharmacology-based study of the active constituents of Chinese medicinal formulae for antitumor mechanism. World J Tradit Chin Med 2018;4:43-53

How to cite this URL:
Zhang BY, Zheng YF, Pang XC, Wang Z, Ding H, Liu AL. Network pharmacology-based study of the active constituents of Chinese medicinal formulae for antitumor mechanism. World J Tradit Chin Med [serial online] 2018 [cited 2018 Nov 20];4:43-53. Available from: http://www.wjtcm.net/text.asp?2018/4/2/43/235826




  Introduction Top


Cancer is generally acknowledged as a life-threatening malignant disease with increasing incidence and mortality rate. According to China's recent statistical data, the death brought by cancer has outnumbered that by cardiovascular disease, and become the most possible factor of death of rural and urban residents.[1],[2] At present, the medical treatment of malignant tumor is mainly about traditional surgical operation, radiotherapy, and chemotherapy. Although radiotherapy can kill tumor cells and inhibit their proliferation in short term and chemotherapy has good effect on some kinds of tumor, the specificity is both quite low; while killing the tumor cells, the therapies also inhibit the activity of the normal cells in human body. Thus, most of the therapies have serious side effects.[3]

Traditional Chinese medical science has recognized the existence of cancer from “Shen nong's herbal classic.” From then on, doctors of traditional Chinese medicine (TCM) in every dynasty devoted themselves to explore ways to cure cancer and left us a large number of formulae, in which about 200 kinds of herbs have been proved to have antitumor effects.[4] Compared to the traditional radiotherapy and chemotherapy in Western medicine, TCM has the advantages of wide source, low price, and little side effects as well as the same antitumor effect. In addition, it can also play an important role in improving immunity, improving patients' quality of life, preventing relapse and metastasis of tumor cells, and extending survival time.[5] In combination with TCM and Western medicine, the use of Chinese herbs can enhance the sensitivity of radiotherapy and chemotherapy and reduce the adverse effects of radiotherapy and chemotherapy. Compared with Western medicine, TCM has unique advantages in individualized treatment, which helps to select suitable drugs for patients and improve treatment pertinence.[6] As a result, TCM has been taken as a common adjuvant therapy in China's hospitals to assist curing cancer.[7]

At present, Chinese medical formula has played an important role in different stages of the treatment of tumor, and its curative effect has been fully affirmed, which made it become one of the hot spots in studies of TCM. TCM has the characteristics of multicomponents, multitargets, and diverse modes of regulation. It is difficult to reflect the systematic [8] TCM by Western single-target and single-component research method, which cannot explain scientifically the material basis and prescription rules of Chinese herbal compound. Hopkins [9] proposed the network pharmacology research method and believed that the drug acts on multiple targets and produces synergistic and attenuating effects through interactions between multiple targets.[10] Network pharmacology studies problems from the perspective of mutual connection, which exactly coincides with the core ideas of TCM. Therefore, the application of network pharmacology to TCM has unique advantages and great potential for development. In the wake of modernization in Chinese medicine these years, several Chinese medicine databases (TCMID, Comparative Toxicogenomics Database [CTD], Traditional Chinese Medicine Systems Pharmacology [TCMSP], HIT, TCMDB at Taiwan, etc.)[11] have been established. Based on data mining on current databases and analysis in bioinformatics together with computational simulation method, we can find a convenient and effective means for uncovering the network mechanism of TCM.

We first collected five main categories of antitumor Chinese medical formulae, which are divided by its function that include strengthening the body resistance, clearing away heat and toxic material, activating blood circulation to dissipate blood stasis, resolving hard lump, and reducing phlegm and dampness. We chose several single herbs from those formulae with top frequency. Then they were analyzed to set up the antitumor material basis. On the basis of collecting herbs' chemical constituents and analyzing its gene regulation effect, we carried out Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis and constructed constituent–gene network, protein–protein interaction network, gene–pathway network, and gene–disease network to explain the network mechanism of the herbs' antitumor effect. At last, the network of chemical constituent–genes was constructed, and based on the corresponding targets of crucial genes, the molecular docking models were established to further confirm the mechanism of chemical constituents against antitumor targets, and therefore provide important information for multitarget drug design in cancer therapy afterward.


  Materials and Methods Top


Chinese medicinal formula and monomers

TCM compound is the basic form of TCM for the prevention and treatment of diseases, that is, a mixture of certain quantitative Chinese herbal plants. TCM compound contains a large number of chemical substances, which are the material basis for the interaction with multiple disease-related targets. The antitumor formulae are collected through the two ways described as follows: (1) Inquire information in the modern application database of prescriptions (http://cowork.cintcm. com/engine/login_do.jsp?u=guestandp=uest321andcnid=12895) with “cancer” or “tumor” as the keywords; (2) Inquire information in CNKI and PubMed databases. On this basis, the frequency of occurrence of each herb was ranked. Four herbs with a frequency of >10 were chosen for further study. All constituents from these four herbs were collected from CNPC (http://pharmdata.ncmi.cn/cnpc/) and TCMSP database (http://ibts.hkbu.edu.hk/LSP/tcmsp.php).

The collection of regulated genes and targets

For the known ingredients of TCMs, we used the TCMID (http://www.megabionet.org/tcmid/)[12] and CTD (http://ctdbase.org/)[13] to analyze their targets. TCMID consists of six parts and they are prescriptions, herbs, ingredients, targets, drugs, and diseases. TCMID identifies the potential interaction between chemical constituents and targets through data mining of STITCH, herb ingredients' targets, and literature. CTD provides the information about constituent–gene/protein interactions, constituent–disease and gene–disease interactions, of which the constituent–gene/protein interaction data are from the reported literature.

Network analysis

We used FunRich 2.1.2 (http://www.funrich.org) to analyze the distribution of genes regulated by active ingredients in Chinese medicines and obtained the co-regulated genes. On the one hand, KEGG and GO enrichment analysis was performed on regulated genes from each herb to analyze the antitumor effect. On the other hand, we constructed the constituent–gene network on the basis of co-regulated genes. The STRING database was used to predict the relationship of genes and construct a protein–protein interaction network. The metabolic pathways regulated by constituents in Chinese medicine were GO, KEGG, and OMIM enrichment analyzed by using DAVID database to construct the gene–pathway network and gene–disease network.

Interaction analysis

Cytohubba is the plug-in component of Cytoscape_3.2.1 and it can help find out the key nodes from the protein–protein interaction network. Pick out the targets of marketed drugs or drugs at Phase II clinical trials to construct molecular docking models. The crystal structures of these target proteins were downloaded from the PDB (Protein Data Bank) database.[14] To ensure the reliability of molecular docking, we chose protein crystal structures containing co-crystallized ligand with a resolution of <2.5 Å to establish molecular docking models. The molecular docking was processed with the Libdock software package of Discovery Studio 2016 (San Diego, CA, USA). Before docking, the co-crystallized water was removed, and the polar hydrogen and incomplete residues were added. The active pocket of the docking is defined by the primitive ligand molecule. After setting the docking parameters, the ligand molecule was extracted from the crystal structure and redocked to the predefined active pocket. The root-mean-square deviation (RMSD) was used to compare differences between the atomic distances of the docked poses and the real co-crystallized pose to measure docking reliability.


  Results Top


Antitumor Chinese medicinal formulae and chemical constituent collection

A total of 65 traditional Chinese medicinal formulae for the treatment of cancer were collected through the modern application database of prescriptions and literature search, which include strengthening the body resistance type compounds, clearing away heat and toxic material type compounds, activating blood circulation to dissipate blood stasis type compounds, resolving hard lump type compounds, and reducing phlegm and dampness type compounds. Then we analyzed the frequency of occurrence of single herbs in these formulae and the results were shown in [Figure 1]. There are four herbs with a frequency of >10, which are licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae. The main chemical constituents contained in the four herbs were collected from China Natural Product Database and TCMSP Database; the active constituents among them were collected from TCMID and CTD Databases. [Table 1] shows the active ingredients statistics of the four herbs.
Figure 1: Frequency of herbs in the Chinese medicinal formula for antitumor therapy

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Table 1: The constituents statistics of the four herbs, licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae

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Antitumor material basis

We studied the antitumor material basis of four herbs, namely licorice, Radix astragali, Panax ginseng, and Radix scutellariae, through the method of literature research.

The triterpenes and flavonoid components from licorice and the extracts from licorice have significant inhibitory effects on colorectal, breast, prostate, liver, stomach, bladder, and lung cancers.[15] Khan et al.[16] pointed out that the constituent glycyrrhizin can significantly reduce the level of tumor necrosis factor-alpha and weaken the mucus layer depletion and the transfer from sialic mucin to sulphomucin; Glycyrrhizin has strong chemopreventive potential for 1,2-dimethylhydrazine-induced colon cancer. There are many literatures studying the antitumor activity of licorice, among which most focus is on the anti-breast cancer activity. Hsu et al.[17] pointed out that the constituent glabridin can inhibit the invasion, metastasis, and angiogenesis of malondialdehyde (MDA)-MB-231 human breast cancer cells by inhibiting the focal adhesion kinase/Rho signaling pathway. Lee et al.[18] found that compound isoangustone A is a potent inhibitor of CDK2 for the treatment of prostate cancer. Lin et al.[19] reported that the constituent glycyrrhetinic acid can effectively inhibit the tumor formation of gastric cancer cells in nude mice by inducing gastric cancer cell apoptosis and arresting the cell cycle in G2 phase. Tsai et al.[20] reported that the constituent licochalcone A can inhibit the migration and invasion of human hepatocellular carcinoma cells SK-Hep-1 and HA22T/VGH. This compound was found to inhibit the activity and expression of uPA and reduce the uPA transcription level in the above cells. Yuan et al.[21] found that the constituent licochalcone B significantly inhibited the proliferation of human bladder cancer T24 and EJ cell lines in a concentration- and time-dependent manner. Tsai et al.[22] reported that the constituent glabridin inhibited the invasion and metastasis of human non-small cell lung cancer A549 cells and reduced A549-mediated angiogenesis by inhibiting the FAK/Rho signaling pathway.

Radix Astragali contains a variety of active ingredients, including polysaccharides, flavonoids, saponins, amino acids, and a variety of trace elements. Its antitumor mechanisms mainly include inhibiting tumor cell proliferation, promoting tumor cell apoptosis, inhibiting tumor cell migration, scavenging free radicals, and enhancing immune function.[23] Li et al.[24] studied the influence of Radix Astragali polysaccharide (APS) on human erythroleukemia K562 cell proliferation and apoptosis, proving that APS may inhibit the proliferation of K562 cells by the downregulation of Cyclin B and Cyclin E and the upregulation of the level of p21. Wang et al.[25] observed the changes of cell cycle and apoptosis rate of BGC-823 cells treated with total flavonoids of Radix Astragali by flow cytometry and found that total flavonoids of Radix Astragali could delay the cell cycle of BGC-823 cells at G0/G1 phase in a dose-dependent manner. The experimental results of Cheng et al.[26] showed that astragaloside reduced the expression of matrix metalloproteinase (MMP-2) and MMP-9 through the pathway of protein kinase C-α-extracellular and regulated protein kinase (ERK1)/2-nuclear factor kappa B, thereby inhibiting the cell metastasis of lung cancer A549. Yin et al.[27] proved that Radix Astragali extract can significantly reduce the expression of cyclooxygenase-2 and vascular endothelial growth factor in stage I tumors, suggesting that Radix Astragali extract can inhibit tumor cell migration. Another study [28],[29] found that astragaloside, calycosin, and formononetin have anti-oxidative activity and can scavenge free radicals. In addition, Radix Astragali injection and its polysaccharides can not only increase superoxide dismutase activity, reduce MDA content, and eliminate reactive oxygen species (ROS) and reactive nitrogen species produced by intracellular oxidative stress, but also reduce free radical generation.[30] Zhang et al.[31] detected the ratio of regulatory T cells (Tregs) and cytotoxic T lymphocytes (CTLs) in mice with lung cancer which were treated by oral administration of astragaloside using flow cytometry and found that the proportion of Treg decreased while the proportion of cytotoxic T lymphocytes (CTLs) increased in the spleen, suggesting that astragaloside may inhibit tumor growth by enhancing immune function.

The main antitumor ingredients in Panax Ginseng mainly include ginsenosides and their metabolites, Panax Ginseng polysaccharides, and Panax Ginseng alkynyl alcohol. According to the currently reported literature, Panax Ginseng has a significant inhibitory effect on liver cancer, stomach cancer, lung cancer, kidney cancer, squamous cell carcinoma, nasopharyngeal cancer, esophageal cancer, colon cancer, gallbladder cancer, melanoma, glioma, breast cancer, papilloma, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, prostate cancer, ascites cancer, lymphoma, myeloma, osteosarcoma, leukemia, and other tumor proliferation.[32] Studies have shown that 20 (S)-ginsenoside Rg3,[33],[34] ginsenoside Rd,[35] PNT,[36] and PNN [37] can inhibit tumor cell mitosis and DNA synthesis in the interphase, as in colon cancer cells, the expression of proliferation-related protein and proliferating cell nuclear antigen is inhibited, leading to the reduction of DNA replication and repair, thereby inhibiting cell proliferation. Ginsenosides such as Rg3,[38] Rg5,[39] CK,[40] and 25-OH-PPD [41] work in the regulation of cell cycle-related proteins such as breast cancer, gastric cancer, lung cancer, and prostate cancer; the tumor cell cycle is arrested in G0/G1 phase in the end. Ginsenosides Rg5,[39] Rh2,[42] Rk1,[43] CK,[40] and PPD [41] can induce endogenous apoptosis of tumor cells. Ginsenosides Rh2,[42] Rk1,[43] CK,[40] and PPD [41] can induce exogenous apoptosis of tumor cells. Currently, Panax Ginseng-induced differentiation of tumor cells is mainly directed against leukemia. Studies have shown that ginsenosides induce leukemia cells to differentiate into erythroid cells by the internalization of the erythropoietin receptor.[44] Another study has shown that active ingredients in Panax Ginseng can significantly inhibit the invasion and metastasis of a variety of tumors. Ginsenosides such as Rb2,[45] Rg1,[46] Rg3,[47],[48] Rh1,[49] Rh2,[50] Rd,[51] and CK [52] can inhibit the invasion and metastasis of cancer cells by inhibiting the expression of MMP-1, 2, 3, 7, 9, 13, and 14 and other MMPs in cancer cells to avoid their destruction of extracellular matrix (ECM) barrier.

The ant-tumor effect of Radix Scutellariae is mainly manifested by flavonoids, including baicalein, baicalin, wogonin, and Oroxylin A, which can affect cell cycle, induce tumor cell apoptosis, and inhibit telomerase activity.[53] It was reported that wogonin can inhibit the proliferation of SK-HEP-1 cells (IC50 =80 μmol/L) and induce the apoptosis of SK-HEP-1 cells and enhance the activity of Caspase-3/cpp32.[54] Wang et al.[55] found that baicalein can induce mitochondria to release cytochrome C in HL-60 cells, resulting in elevated levels of H2O2 in cells, thereby inducing apoptosis and DNA fracture. The catalase can effectively block baicalein-induced apoptosis and DNA fragmentation, indicating that baicalein may induce cell apoptosis through ROS-mediated mitochondrial dysfunction. Baicalein, baicalin, and wogonin can inhibit liver tumor cell HepG2, Hep3B, and SK-HEP1 proliferation. All the three constituents can block the cell cycle of HepG2 cells in G2/M phase and Hep3B cells in G1 subphase. Baicalein and wogonin block the cell cycle of SK-HEP1 cells in G1 and G1 phases, respectively.[56],[57],[58] Huang et al.[59] found that the inhibitory effect of wogonin on the proliferation of HL-60 cells (IC50 = 50 μmol/L) was related to the decrease of telomerase activity. Zhang et al.[60] found that the tumor volume was significantly reduced and the tumor growth inhibition rate was 66% in HNSCC model mice fed with flavonoids from Radix Scutellariae. Administered with Oroxylin A (40 mg/kg), the tumor volume of melanoma B16-F10 mice was reduced by 73%.[61]

Enrichment analysis of the regulated gene

According to TCMID and CTD databases, the number of genes regulated by active ingredients from licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae is 521, 576, 208, and 678, respectively. There are 80 genes co-regulated by the four herbs [Figure 2]. The genes from the four herbs undergo KEGG pathway enrichment analysis, and five pathways are listed in [Table 2] according to the number of enriched genes and P value. All the pathways in [Table 2] have been reported in the literature, which shows our experimental results are reliable. The four herbs share some similarities in pathways and they all act on the toll-like receptor signaling pathway. Moreover, licorice acts more similar with Panax Ginseng and Radix Astragali acts more similar with Radix Scutellariae. Using Funrich 2.1.2, their GO pathways and molecular functions were enriched. [Figure 3] shows that licorice and Panax Ginseng mainly act on serine proteases activity, while Radix Astragali and Radix Scutellariae mainly have effects on tyrosine kinase activity and transcription factors activity, respectively. From the GO_BP enrichment analysis [Figure 4], we can see that all of the four herbs have a great influence on both energy and metabolic pathways.
Figure 2: Venn diagram of genes related to the four herbs for antitumor mechanism

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Table 2: Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the regulated gene of Licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae

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Figure 3: (a) Gene ontology molecular function enrichment for Licorice, (b) Radix Astragali, (c) Panax Ginseng, and (d) Radix Scutellariae

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Figure 4: (a) Gene ontology biological process for Licorice, (b) Radix Astragali, (c) Panax Ginseng, and (d) Radix Scutellariae

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Analysis of network mechanism

Venn diagram [Figure 2] shows the four single herbs' co-regulated 80 genes, indicating that they share a common antitumor mechanism. Therefore, we enrichment analyzed the 80 genes to illustrate the regulation effects of chemical constituents on related diseases and the relationship between pathways and related diseases. [Figure 5] shows that most of the chemical constituents can regulate multiple genes, which are potential multitarget chemicals. [Figure 6] shows the common pathways regulated by these genes, including toll-like receptor signaling pathway, p53 signaling pathway, adipocytokine signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and T-cell-related immune signaling pathway. From [Figure 7], we can find that these herbs are involved in a variety of cancers, such as prostate cancer, breast cancer, and melanoma. What's more, these four herbs also have effects on the signaling pathways related to Alzheimer's disease and type II diabetes.
Figure 5: The constituent − gene network for potential regulators in Licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae (threshold: count = 2, P < 0.05). The blue circle means gene and the green circle means constituent

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Figure 6: The enrichment analysis of gene–pathway network by Kyoto Encyclopedia of Genes and Genomes (threshold: count = 2, P < 0.05). The blue square means gene and the purple square means Kyoto Encyclopedia of Genes and Genomes Pathway

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Figure 7: The interaction analysis of gene–disease network (threshold: count = 2, P < 0.05). The blue circle means gene and the brown circle means disease

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Molecular docking

Through gene–gene interaction [Figure 8] and hub gene analysis, we identified nine targets with either marketed drugs or drugs at phase II clinical trials. They are PTG2, epidermal growth factor receptor (EGFR), peroxisome proliferator-activated receptor gamma, estrogen receptor 1 (ESR1), mammalian target of rapamycin (MTOR), AKT1, MAPK1, peroxisome proliferator-activated receptor alpha, and MAPK8. We reveal the interaction of chemical constituents and targets by molecular docking model. Before the molecular docking between the chemical constituent and the target is conducted, the ligand in the target crystal structure is verified by re-docking. The spatial coordinates of the docked ligand and the ligand in the target are compared to get the RMSD value. When RMSD is <2.5, it indicates that the docking results are reliable [Table 3]. Furthermore, based on the chemical constituent–gene regulation network shown in [Figure 5], we investigate the interaction of these valid chemical compositions with nine core targets. [Table 4] shows the information of the top five chemical components after each target is docked. Most of the compounds can act on multiple targets, such as narcissin, rutin, dauricine, scutellarin, baicalin, isoschaftoside, leucovorin, and pseudo-hypericin, whose structures mainly belong to alkaloids, flavonoids and their glycosides, organic acids, or dianthrone. These scaffolds provide the structural basis for multitarget compound design. Taking lycorine with the most frequent occurrence as an example, we studied its interaction with multiple targets. [Figure 9] exemplifies that narcissin binds to multiple targets via hydrogen bonds, Pi bonds, and the attraction between ions.
Figure 8: The analysis of gene–gene interaction network by STRING (edge value cutoff of 0.70). The red triangles mean hub genes and were used for molecular docking

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Table 3: The target used for docking and their protein data bank ID, resolution, and root-mean-square deviation for validation

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Table 4: The top five constituents with highest docking scores of each target

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Figure 9: (a) Narcissin has a wide interaction with multiple targets, including estrogen receptor 1, (b) mitogen-activated protein kinase/JNK1, (c) epidermal growth factor receptor, (d) AKT1, (e) mammalian target of rapamycin and (f) MAKP1/ERK2. The binding modes and docking scores were listed

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  Discussion and Conclusion Top


As a major component of traditional medicine, TCM has played an important role in cancer prevention over thousands of years. However, since the composition of TCM is complicated and tumor is also a multifactor complex disease, the pharmacological mechanism of Chinese medicine for cancer treatment is not yet clear. The chemical compositions from licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae are complex, mainly including triterpenes, flavonoids, polysaccharides, saponins, amino acids, and acetylenic alcohols; they all showed good antitumor activity, which laid a good material foundation for the study of pharmacological network mechanism of these four herbs.

In this article, we explore the antitumor mechanism of four representative single herbs, namely, licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae through the data mining and computational simulation and other methods. The gene enrichment results showed that licorice and Panax Ginseng activate the immune response and enhance immune function by affecting toll-like and Nucleotide oligomerization domain (NOD)-like receptor signaling pathways. Licorice is closely related to the synthesis of steroid hormones, which can explain why there are so many reports about anti-breast cancer activity of Licorice. What's more, we found that licorice can act on a variety of CYP450, which makes licorice an antidote, helping ease the drug potent. However, we should also pay attention to the combination of licorice and Western medicine to avoid the side effects caused by the induction or inhibition of metabolism. In addition to the pathways directly related to cancer, the chemical compositions from Panax Ginseng can also affect the adipokine signaling pathway. Recent studies show that adipose tissue is a metabolically active secretion organ and can secrete a variety of tumor-associated adipokines. In the process of multiple types of tumor progression, adipocyte metabolism and secretion in the tumor microenvironment have received extensive attention. Tumor occurrence and metastasis are closely related to the microenvironment.[82] Therefore, the effect of Panax Ginseng in adipokine signaling pathway provides a new direction for its antitumor mechanism. By KEGG and GO enrichment analysis, we found that Radix Astragali can inhibit tumor cell proliferation, promote tumor cell apoptosis, inhibit tumor cell migration, and enhance the immune function through affecting apoptosis pathway, p53 signaling pathway, cell adhesion, and toll-like signal transduction pathway, which are consistent with the literature. What's more, we also found that Radix Astragali can significantly affect the adipokine signaling pathway and tumor microenvironment.

Through the analysis of 80 core genes co-regulated by four single herbs, we found that the regulation of chemical compositions toward gene is a many-to-many relationship. Multicomponent Chinese traditional medicine and multigene regulation mechanism determine its broad-spectrum antitumor effect. [Figure 7] shows that these four herbs have effects on a variety of tumors including prostate cancer, small cell lung cancer, thyroid cancer, kidney cancer, colon cancer, melanoma, endometrial cancer, chronic myeloid leukemia, pancreatic cancer, and bladder cancer. In addition, these four herbs also have regulatory effects on Alzheimer's disease and type II diabetes, which may be related to their regulation of energy metabolism; energy metabolism is closely related to cancer, Alzheimer's disease, and diabetes. We can summarize several antitumor mechanisms of TCM from [Figure 6]: (1) Activate immune response and improve immunity by regulating B-cells, T-cells, and toll-like, NOD-like receptor signaling pathways. (2) Improve tumor microenvironment by regulating adipokines, inflammatory factors, and cell–cell adhesions. (3) Regulate tumor cell proliferation, migration, differentiation, and apoptosis by regulating tumor suppressor p53 and kinase-related metabolic pathways.

What's more, through the analysis of gene interaction networks, several key antitumor targets of licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae were identified, which are also the current representative targets for the treatment of cancer. From the molecular docking results, we can see that most of the chemical components from the four single herbs have some effects on these key targets and there are many constituents acting on multiple targets. These chemical constituents are important material bases for the antitumor effects of TCM and for the study of their mechanism of action, also providing important information for antitumor drug design with multiple targets.

This work is different from many of the previous network pharmacology-based TCM studies.[83],[84] Instead of conducting generic screening of compounds of TCM, we studied the antitumor effects of all chemical components and avoided the omission of the pharmacologically active compound backbone. In addition, we constructed a gene–disease network and found that these TCM is associated with a variety of cancers and also plays a role in signaling pathways associated with other diseases such as Alzheimer's disease. Finally, we not only set up networks to make predictions, but also discovered chemical constituents that act on multiple targets through molecular docking. These chemical constituents are important material bases for the antitumor effects of TCM and for the study of their mechanism of action, also providing important information for antitumor drug design with multiple targets.

In summary, we proposed an analysis method for identification of the molecular mechanisms of herbal formula based on the integration of multicomponent effects. Dependent on the collected Chinese medicinal formulae for cancer treatment, several single herbs with the top frequency were selected for further study. To explain the synergistic mechanism of various active ingredients of Chinese medicinal formula, the constituent–gene network, protein–protein interaction network, gene–pathway enrichment network, and gene–disease network were constructed on the basis of the analysis of constituents and relatively regulated genes of licorice, Radix Astragali, Panax Ginseng, and Radix Scutellariae using data mining method. The research method of this article will provide reference for the study of antitumor mechanism of other single herbs. The multitarget active chemical constituents found in the study will provide important information for the design of new antitumor drugs, and meanwhile this study will lay theoretical basis for clinical application of antitumor drugs.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (81673480), Beijing Natural Science Foundation (7152103), National Population and Health Scientific Data Sharing Service Platform (2016NCMIZX05, NCMI-AGD05-201709), and CAMS Initiative for Innovative Medicine (CAMS-I2M) (2016-I2M-3-007).

Conflicts of interest

There are no conflicts of interest.



 
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