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An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology

Received: 10 April 2020     Accepted: 6 May 2020     Published: 19 May 2020
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Abstract

BACKGROUND: Danshen, also known as Salvia miltiorrhiza or radix salvia in Latin, is an important drug whose main pharmacological effects are vasodilation, promotion of blood circulation, and elimination of stasis. In recent years, it has been reported that danshen also has anti-tumor activity. OBJECTIVE: The aim of this study was to explore the feasibility and potential mechanism of S. miltiorrhiza in the treatment of gastric cancer. STUDY DESIGN: We analyzed effective components and target genes of S. miltiorrhiza in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to gastric cancer and the intersection of these genes with the active components of S. miltiorrhiza. Target genes related to gastric cancer were taken as common potential target genes of S. miltiorrhiza, which could act on gastric cancer. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of S. miltiorrhiza in the treatment of gastric cancer was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of S. miltiorrhiza in the treatment of gastric cancer. RESULTS: We extracted a total of 65 active components from S. miltiorrhiza, including dihydrotanshinone I and miltionones I and II, as well as 102 potential target genes for gastric cancer. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were protein kinase B1 (AKT1), interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), Fos, mitogen-activated protein kinase 1 (MAPK1), Myc, JUN, Caspase-3 (CASP3), and signal transducer and activator of transcription 3 (STAT3). Pathway enrichment mainly involved signaling pathways such as phosphoinositide 3-kinase (PI3K)–Akt, hypoxia-inducible factor 1 (HIF-1), and IL-17. CONCLUSION: Based on network pharmacology, S. miltiorrhiza is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of gastric cancer. Its mechanism for treating this cancer operates via multiple components and pathways. This study provides the basic theory and the basis for further research.

Published in Journal of Cancer Treatment and Research (Volume 8, Issue 2)
DOI 10.11648/j.jctr.20200802.12
Page(s) 34-44
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2020. Published by Science Publishing Group

Keywords

Salvia miltiorrhiza, Gastric Cancer, Network Pharmacology, Target Gene, GO Function Enrichment Analysis, KEGG Pathway Enrichment Analysis

References
[1] D. Yang, X. Wang, W. Yuan, and Z. Chen. "Intake of Anthocyanins and Gastric Cancer Risk: A Comprehensive Meta-Analysis on Cohort and Case-Control Studies," J Nutr Sci Vitaminol (Tokyo), vol. 65, no. 1, 2019, pp. 72-81.
[2] D. D. Xiong, C. M. Zeng, L. Jiang, D. Z. Luo, and G. Chen. "Ki-67/MKI67 as a Predictive Biomarker for Clinical Outcome in Gastric Cancer Patients: an Updated Meta-analysis and Systematic Review involving 53 Studies and 7078 Patients," J Cancer, vol. 10, no. 22, 2019, pp. 5339-5354.
[3] S. Yin, P. Wang, X. Xu, Y. Tan, J. Huang, and H. Xu. "The optimal strategy of multimodality therapies for resectable gastric cancer: evidence from a network meta-analysis," J Cancer, vol. 10, no. 14, 2019, pp. 3094-3101.
[4] B. Zhao, J. Zhang, J. Zhang, et al. "The Impact of Preoperative Underweight Status on Postoperative Complication and Survival Outcome of Gastric Cancer Patients: A Systematic Review and Meta-analysis," Nutr Cancer, vol. 70, no. 8, 2018, pp. 1254-1263.
[5] C. Zhang, W. Hou, J. Huang, et al. "Effects of metastasectomy and other factors on survival of patients with ovarian metastases from gastric cancer: a systematic review and meta-analysis," J Cell Biochem, vol. 120, no. 9, 2019, pp. 14486-14498.
[6] D. Zhu, X. Shi, S. Nicholas, Q. Bai, and P. He. "Impact of China's healthcare price reforms on traditional Chinese medicine public hospitals in Beijing: an interrupted time-series study," BMJ Open, vol. 9, no. 8, 2019, p. e029646.
[7] J. Zheng, G. Li, and Q. Sun. "Misuse of traditional Chinese medicine may be a risk factor to tumorigenesis and progression of head and neck carcinoma in China: a hypothesis based on a case series," J BUON, vol. 24, no. 3, 2019, pp. 1296-1300.
[8] D. D. Xiong, Y. Qin, W. Q. Xu, et al. "A Network Pharmacology-Based Analysis of Multi-Target, Multi-Pathway, Multi-Compound Treatment for Ovarian Serous Cystadenocarcinoma," Clin Drug Investig, vol. 38, no. 10, 2018, pp. 909-925.
[9] X. Zhang, D. Wang, X. Ren, A. G. Atanasov, R. Zeng, and L. Huang. "System Bioinformatic Approach Through Molecular Docking, Network Pharmacology and Microarray Data Analysis to Determine the Molecular Mechanism Underlying the Effects of Rehmanniae Radix Praeparata on Cardiovascular Diseases," Curr Protein Pept Sci, vol. 20, no. 10, 2019, pp. 964-975.
[10] H. Zhang, Z. Y. Yan, Y. X. Wang, et al. "Network pharmacology-based screening of the active ingredients and potential targets of the genus of Pithecellobium marthae (Britton & Killip) Niezgoda & Nevl for application to Alzheimer's disease," Nat Prod Res, vol. 33, no. 16, 2019, pp. 2368-2371.
[11] J. Xue, Y. Shi, C. Li, and H. Song. "Network pharmacology-based prediction of the active ingredients, potential targets, and signaling pathways in compound Lian-Ge granules for treatment of diabetes," J Cell Biochem, vol. 120, no. 4, 2019, pp. 6431-6440.
[12] C. C. Su. "Tanshinone IIA decreases the migratory ability of AGS cells by decreasing the protein expression of matrix metalloproteinases, nuclear factor kappaB-p65 and cyclooxygenase-2," Mol Med Rep, vol. 13, no. 2, 2016, pp. 1263-1268.
[13] T. Wang and X. Fu. "Danshen Formulae for Cancer: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials". Evid Based Complement Alternat Med, vol. 2019, p. 2310639. https://doi.org/10.1155/2019/2310639.
[14] J. Liu, J. J. Mao, X. S. Wang, and H. Lin. "Evaluation of Traditional Chinese Medicine Herbs in Oncology Clinical Trials," Cancer J, vol. 25, no. 5, 2019, pp. 367-371.
[15] Y. Li, Z. Liu, J. Li, and M. Wang. "Traditional Chinese medicine, Kami-Shoyo-San protects ketamine-induced neurotoxicity in human embryonic stem cell-differentiated neurons through activation of brain-derived neurotrophic factor," Neuroreport, vol. 30, no. 16, 2019, pp. 1102-1109.
[16] H. Y. Zhang, H. L. Wang, G. Y. Zhong, and J. X. Zhu. "Molecular mechanism and research progress on pharmacology of traditional Chinese medicine in liver injury," Pharm Biol, vol. 56, no. 1, 2018, pp. 594-611.
[17] C. Liu, S. Yang, K. Wang, et al. "Alkaloids from Traditional Chinese Medicine against hepatocellular carcinoma," Biomed Pharmacother, vol. 120, 2019, p. 109543.
[18] J. Ru, P. Li, J. Wang, et al. "TCMSP: a database of systems pharmacology for drug discovery from herbal medicines," J Cheminform, vol. 6, 2014, p. 13.
[19] N. Rappaport, S. Fishilevich, R. Nudel, et al. "Rational confederation of genes and diseases: NGS interpretation via GeneCards, MalaCards and VarElect," Biomed Eng Online, vol. 16, no. Suppl 1, 2017, p. 72.
[20] Y. S. Qiu, G. J. Liao, and N. N. Jiang. "REG3A overexpression suppresses gastric cancer cell invasion, proliferation and promotes apoptosis through PI3K/Akt signaling pathway," Int J Mol Med, vol. 41, no. 6, 2018, pp. 3167-3174.
[21] J. Chen, G. Q. Li, L. Zhang, et al. "Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression," Cancer Lett, vol. 412, 2018, pp. 30-36.
[22] D. Qiao, Y. Li, J. Xing, et al. "[Baicalein inhibits PI3K/AKT signaling pathway and induces autophagy of MGC-803 cells]," Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, vol. 35, no. 7, 2019, pp. 613-618.
[23] H. Qiu, G. Hu, and H. Xiong. "Establishment and characterization of chronic-hypoxia-resistant gastric cancer cell line MNK45/HYP," J Huazhong Univ Sci Technolog Med Sci, vol. 31, no. 1, 2011, pp. 52-57.
[24] Y. Kato, M. Yashiro, Y. Fuyuhiro, et al. "Effects of acute and chronic hypoxia on the radiosensitivity of gastric and esophageal cancer cells," Anticancer Res, vol. 31, no. 10, 2011, pp. 3369-3375.
[25] L. F. Dong, S. Y. Xu, J. P. Long, F. Wan, and Y. D. Chen. "RNA-Sequence Analysis Reveals Differentially Expressed Genes (DEGs) in Patients Exhibiting Different Risks of Tumor Metastasis," Med Sci Monit, vol. 23, 2017, pp. 2842-2849.
[26] C. Y. Zhu, F. Q. Meng, and J. Liu. "MicroRNA-524-5p suppresses cell proliferation and promotes cell apoptosis in gastric cancer by regulating CASP3," Eur Rev Med Pharmacol Sci, vol. 23, no. 18, 2019, pp. 7968-7977.
[27] T. P. Xu, P. Ma, W. Y. Wang, et al. "KLF5 and MYC modulated LINC00346 contributes to gastric cancer progression through acting as a competing endogeous RNA and indicates poor outcome," Cell Death Differ, vol. 26, no. 11, 2019, pp. 2179-2193.
[28] L. O. Lopes, J. H. Maues, H. Ferreira-Fernandes, et al. "New prognostic markers revealed by RNA-Seq transcriptome analysis after MYC silencing in a metastatic gastric cancer cell line," Oncotarget, vol. 10, no. 56, 2019, pp. 5768-5779.
[29] Y. Yuan, Z. Ding, J. Qian, et al. "Casp3/7-Instructed Intracellular Aggregation of Fe3O4 Nanoparticles Enhances T2 MR Imaging of Tumor Apoptosis," Nano Lett, vol. 16, no. 4, 2016, pp. 2686-2691.
[30] Z. Wang, F. Zou, Y. Tian, B. Xiang, B. Qin, and Y. Liu. "Paclitaxel reversed trastuzumab resistance via regulating JUN in human gastric cancer cells identified by FAN analysis," Future Oncol, vol. 14, no. 26, 2018, pp. 2701-2712.
[31] P. Chen, X. Luo, Z. Che, et al. "Targeting of the C-Jun/BCL-XL/P21 Axis Accelerates the Switch from Senescence to Apoptosis Upon ROC1 Knockdown in Gastric Cancer Cells," Cell Physiol Biochem, vol. 48, no. 3, 2018, pp. 1123-1138.
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    Xiongdong Zhong. (2020). An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology. Journal of Cancer Treatment and Research, 8(2), 34-44. https://doi.org/10.11648/j.jctr.20200802.12

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    Xiongdong Zhong. An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology. J. Cancer Treat. Res. 2020, 8(2), 34-44. doi: 10.11648/j.jctr.20200802.12

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    AMA Style

    Xiongdong Zhong. An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology. J Cancer Treat Res. 2020;8(2):34-44. doi: 10.11648/j.jctr.20200802.12

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  • @article{10.11648/j.jctr.20200802.12,
      author = {Xiongdong Zhong},
      title = {An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology},
      journal = {Journal of Cancer Treatment and Research},
      volume = {8},
      number = {2},
      pages = {34-44},
      doi = {10.11648/j.jctr.20200802.12},
      url = {https://doi.org/10.11648/j.jctr.20200802.12},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jctr.20200802.12},
      abstract = {BACKGROUND: Danshen, also known as Salvia miltiorrhiza or radix salvia in Latin, is an important drug whose main pharmacological effects are vasodilation, promotion of blood circulation, and elimination of stasis. In recent years, it has been reported that danshen also has anti-tumor activity. OBJECTIVE: The aim of this study was to explore the feasibility and potential mechanism of S. miltiorrhiza in the treatment of gastric cancer. STUDY DESIGN: We analyzed effective components and target genes of S. miltiorrhiza in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to gastric cancer and the intersection of these genes with the active components of S. miltiorrhiza. Target genes related to gastric cancer were taken as common potential target genes of S. miltiorrhiza, which could act on gastric cancer. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of S. miltiorrhiza in the treatment of gastric cancer was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of S. miltiorrhiza in the treatment of gastric cancer. RESULTS: We extracted a total of 65 active components from S. miltiorrhiza, including dihydrotanshinone I and miltionones I and II, as well as 102 potential target genes for gastric cancer. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were protein kinase B1 (AKT1), interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), Fos, mitogen-activated protein kinase 1 (MAPK1), Myc, JUN, Caspase-3 (CASP3), and signal transducer and activator of transcription 3 (STAT3). Pathway enrichment mainly involved signaling pathways such as phosphoinositide 3-kinase (PI3K)–Akt, hypoxia-inducible factor 1 (HIF-1), and IL-17. CONCLUSION: Based on network pharmacology, S. miltiorrhiza is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of gastric cancer. Its mechanism for treating this cancer operates via multiple components and pathways. This study provides the basic theory and the basis for further research.},
     year = {2020}
    }
    

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  • TY  - JOUR
    T1  - An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology
    AU  - Xiongdong Zhong
    Y1  - 2020/05/19
    PY  - 2020
    N1  - https://doi.org/10.11648/j.jctr.20200802.12
    DO  - 10.11648/j.jctr.20200802.12
    T2  - Journal of Cancer Treatment and Research
    JF  - Journal of Cancer Treatment and Research
    JO  - Journal of Cancer Treatment and Research
    SP  - 34
    EP  - 44
    PB  - Science Publishing Group
    SN  - 2376-7790
    UR  - https://doi.org/10.11648/j.jctr.20200802.12
    AB  - BACKGROUND: Danshen, also known as Salvia miltiorrhiza or radix salvia in Latin, is an important drug whose main pharmacological effects are vasodilation, promotion of blood circulation, and elimination of stasis. In recent years, it has been reported that danshen also has anti-tumor activity. OBJECTIVE: The aim of this study was to explore the feasibility and potential mechanism of S. miltiorrhiza in the treatment of gastric cancer. STUDY DESIGN: We analyzed effective components and target genes of S. miltiorrhiza in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to gastric cancer and the intersection of these genes with the active components of S. miltiorrhiza. Target genes related to gastric cancer were taken as common potential target genes of S. miltiorrhiza, which could act on gastric cancer. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of S. miltiorrhiza in the treatment of gastric cancer was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of S. miltiorrhiza in the treatment of gastric cancer. RESULTS: We extracted a total of 65 active components from S. miltiorrhiza, including dihydrotanshinone I and miltionones I and II, as well as 102 potential target genes for gastric cancer. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were protein kinase B1 (AKT1), interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), Fos, mitogen-activated protein kinase 1 (MAPK1), Myc, JUN, Caspase-3 (CASP3), and signal transducer and activator of transcription 3 (STAT3). Pathway enrichment mainly involved signaling pathways such as phosphoinositide 3-kinase (PI3K)–Akt, hypoxia-inducible factor 1 (HIF-1), and IL-17. CONCLUSION: Based on network pharmacology, S. miltiorrhiza is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of gastric cancer. Its mechanism for treating this cancer operates via multiple components and pathways. This study provides the basic theory and the basis for further research.
    VL  - 8
    IS  - 2
    ER  - 

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Author Information
  • Department of General Surgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, P. R. China

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