Skip to main content

Advertisement

SpringerLink
Log in

Network Pharmacology Analysis to Uncover the Potential Mechanisms of Lycium barbarum on Colorectal Cancer

  • Original research article
  • Published:
Interdisciplinary Sciences: Computational Life Sciences Aims and scope Submit manuscript

Abstract

Background

Studies have shown that extracts from Lycium barbarum exerted protective effects against colorectal cancer (CRC) cells. We used the network pharmacology method to determine the effects of L. barbarum on CRC and to predict core targets, biological functions, pathways, and mechanisms of action.

Method

We obtained the active compounds and their targets in L. barbarum via use of the Traditional Chinese Medicine System Pharmacology Database (TCMSP), gathered the CRC targets from Malacards, TTD, GeneCards, and DisGeNET, and chosen the overlapped targets as the candidate targets. After protein–protein interaction (PPI) network analysis, 20 with the highest node degree were selected as the core targets, and their enrichment and pathways were analyzed. Furthermore, we employed iGEMDOCK to validate the compound-target relation.

Result

Eventually, 103 overlapped targets were chosen as the candidate targets. Targets with the top 20 highest node degree were selected as the core targets. Gene Ontology (GO) enrichment analysis indicated that the core targets were enriched in cell proliferation regulation, extracellular space, cytokine receptor binding, and so on. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis proved that the core targets were significantly enriched in bladder cancer, pathways in cancer. The docking results demonstrated that beta-sitosterol, glycitein, and quercetin had good binding activity to CRC putative targets.

Conclusion

Our work successfully predicted the functioning ingredients and potential targets of L. barbarum in CRC and illustrated the potential pathways and mechanisms comprehensively. Nevertheless, these results still call for in vitro and in vivo experiments to validate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Fedewa SA et al (2017) Colorectal cancer statistics, 2017. CA Cancer J Clin 67(3):177–193. https://doi.org/10.3322/caac.21395

    Article  PubMed  Google Scholar 

  2. Pardamean B, Baurley JW, Pardamean CI et al (2016) Changing colorectal cancer trends in Asians. Int J Colorectal Dis 31(8):1537–1538. https://doi.org/10.1007/s00384-016-2564-z

    Article  PubMed  Google Scholar 

  3. Howlader N, Noone AM, Krapcho M et al (2016) SEER cancer statistics review, 1975–2013, National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/archive/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016

  4. Dekker E, Tanis PJ, Vleugels J et al (2019) Colorectal cancer. Lancet 394(10207):1467–1480. https://doi.org/10.1016/S0140-6736(19)32319-0

    Article  PubMed  Google Scholar 

  5. Mao F, Xiao B, Jiang Z et al (2011) Anticancer effect of Lycium barbarum polysaccharides on colon cancer cells involves G0/G1 phase arrest. Med Oncol (Northwood, London, England) 28(1):121–126. https://doi.org/10.1007/s12032-009-9415-5

    Article  CAS  Google Scholar 

  6. Li W, Gao M, Han T (2020) Lycium barbarum polysaccharides ameliorate intestinal barrier dysfunction and inflammation through the MLCK-MLC signaling pathway in Caco-2 cells. Food Funct 11(4):3741–3748. https://doi.org/10.1039/d0fo00030b

    Article  CAS  PubMed  Google Scholar 

  7. Cui F, Shi CL, Zhou XJ et al (2020) Lycium barbarum polysaccharide extracted from Lycium barbarum leaves ameliorates asthma in mice by reducing inflammation and modulating gut microbiota. J Med Food 23(7):699–710. https://doi.org/10.1089/jmf.2019.4544

    Article  CAS  PubMed  Google Scholar 

  8. Ceccarini MR, Vannini S, Cataldi S et al (2016) In vitro protective effects of Lycium barbarum berries cultivated in Umbria (Italy) on human hepatocellular carcinoma cells. Biomed Res Int. https://doi.org/10.1155/2016/7529521

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cassileth B (2010) Lycium (Lycium barbarum). Oncology (Williston Park, N.Y.) 24(14):1353 (PMID: 21294484)

    Google Scholar 

  10. Georgiev KD, Slavov IJ, Iliev IA (2019) Antioxidant activity and antiproliferative effects of Lycium barbarum’s (Goji berry) fractions on breast cancer cell lines. Folia Med 61(1):104–112. https://doi.org/10.2478/folmed-2018-0053

    Article  CAS  Google Scholar 

  11. Wang W, Liu M, Wang Y et al (2018) Lycium barbarum polysaccharide promotes maturation of dendritic cell via notch signaling and strengthens dendritic cell mediated T lymphocyte cytotoxicity on colon cancer cell CT26-WT. Evid Based Complement Altern Med eCAM. https://doi.org/10.1155/2018/2305683

    Article  Google Scholar 

  12. Hsu HJ, Huang RF, Kao TH et al (2017) Preparation of carotenoid extracts and nanoemulsions from Lycium barbarum L. and their effects on growth of HT-29 colon cancer cells. Nanotechnology 28(13):135103. https://doi.org/10.1088/1361-6528/aa5e86

    Article  CAS  PubMed  Google Scholar 

  13. Qingqing Y et al (2016) Laws of medicinal herbs application in traditional Chinese medicine treatment of advanced colorectal cancer. China J Chin Med. https://doi.org/10.16368/j.issn.1674-8999.2016.01.002

    Article  Google Scholar 

  14. Zhang GB, Li QY, Chen QL et al (2013) Network pharmacology: a new approach for Chinese herbal medicine research. Evid Based Complement Altern Med 2013:621423. https://doi.org/10.1155/2013/621423

    Article  Google Scholar 

  15. Yuan H, Ma Q, Cui H et al (2017) How can synergism of traditional medicines benefit from network pharmacology? Molecules. https://doi.org/10.3390/molecules22071135

    Article  PubMed  PubMed Central  Google Scholar 

  16. Li S, Zhang B (2013) Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med 11(2):110–120. https://doi.org/10.1016/S1875-5364(13)60037-0

    Article  PubMed  Google Scholar 

  17. Zheng J, Wu M, Wang H et al (2018) Network pharmacology to unveil the biological basis of health-strengthening herbal medicine in cancer treatment. Cancers (Basel). https://doi.org/10.3390/cancers10110461

    Article  PubMed Central  Google Scholar 

  18. Guo Y, Bao C, Ma D et al (2019) Network-based combinatorial CRISPR-Cas9 screens identify synergistic modules in human cells. ACS Synth Biol 8(3):482–490. https://doi.org/10.1021/acssynbio.8b00237

    Article  CAS  PubMed  Google Scholar 

  19. Ru J, Li P, Wang J et al (2014) TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 6:13. https://doi.org/10.1186/1758-2946-6-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rappaport N, Twik M, Plaschkes I et al (2017) MalaCards: an amalgamated human disease compendium with diverse clinical and genetic annotation and structured search. Nucleic Acids Res 45(D1):D877–D887. https://doi.org/10.1093/nar/gkw1012

    Article  CAS  PubMed  Google Scholar 

  21. Wang Y, Zhang S, Li F et al (2019) Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res. https://doi.org/10.1093/nar/gkz981

    Article  PubMed  PubMed Central  Google Scholar 

  22. Stelzer G, Rosen N, Plaschkes I et al (2016) The GeneCards Suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinform 54:1301–13033

    Article  Google Scholar 

  23. Piñero J, Bravo À, Queralt-Rosinach N et al (2017) DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 45(D1):D833–D839. https://doi.org/10.1093/nar/gkw943

    Article  CAS  PubMed  Google Scholar 

  24. Szklarczyk D, Morris JH, Cook H et al (2017) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res 45(D1):D362–D368. https://doi.org/10.1093/nar/gkw937

    Article  CAS  PubMed  Google Scholar 

  25. Shannon P, Markiel A, Ozier O et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504. https://doi.org/10.1101/gr.1239303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57. https://doi.org/10.1038/nprot.2008.211

    Article  CAS  Google Scholar 

  27. Burley SK, Berman HM, Bhikadiya C et al (2019) RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res 47:D464–D474. https://doi.org/10.1093/nar/gky1004

    Article  CAS  PubMed  Google Scholar 

  28. Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612. https://doi.org/10.1002/jcc.20084

    Article  CAS  PubMed  Google Scholar 

  29. Yang JM, Chen CC (2004) GEMDOCK: a generic evolutionary method for molecular docking. Proteins 55(2):288–304. https://doi.org/10.1002/prot.20035

    Article  CAS  PubMed  Google Scholar 

  30. Bin Sayeed MS, Ameen SS (2015) Beta-sitosterol: a promising but orphan nutraceutical to fight against cancer. Nutr Cancer 67(8):1214–1220. https://doi.org/10.1080/01635581.2015.1087042

    Article  CAS  PubMed  Google Scholar 

  31. Huang J, Xu M, Fang Y et al (2017) Association between phytosterol intake and colorectal cancer risk: a case–control study. Br J Nutr 117(6):839–850. https://doi.org/10.1017/S0007114517000617

    Article  CAS  PubMed  Google Scholar 

  32. Yuan L, Zhang F, Shen M et al (2019) Phytosterols suppress phagocytosis and inhibit inflammatory mediators via ERK pathway on LPS-triggered inflammatory responses in RAW264.7 macrophages and the correlation with their structure. Foods (Basel, Switzerland) 8(11):582. https://doi.org/10.3390/foods8110582

    Article  CAS  Google Scholar 

  33. Lee I, Kim E, Kim D (2012) Inhibitory effect of β-sitosterol on TNBS-induced colitis in mice. Planta Med 78(9):896–898. https://doi.org/10.1055/s-0031-1298486

    Article  CAS  PubMed  Google Scholar 

  34. Dolai N, Kumar A, Islam A et al (2016) Apoptogenic effects of β-sitosterol glucoside from Castanopsis indica leaves. Nat Prod Res 30(4):482–485. https://doi.org/10.1080/14786419.2015.1023201

    Article  CAS  PubMed  Google Scholar 

  35. Sharmila R, Sindhu G (2017) Evaluate the antigenotoxicity and anticancer role of β-sitosterol by determining oxidative DNA damage and the expression of phosphorylated mitogen-activated protein kinases’, C-fos, C-jun, and endothelial growth factor receptor. Pharmacogn Mag 13(49):95–101. https://doi.org/10.4103/0973-1296.197634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zang Y, Feng Y, Luo Y et al (2019) Glycitein induces reactive oxygen species-dependent apoptosis and G0/G1 cell cycle arrest through the MAPK/STAT3/NF-κB pathway in human gastric cancer cells. Drug Dev Res 80(5):573–584. https://doi.org/10.1002/ddr.21534

    Article  CAS  PubMed  Google Scholar 

  37. Wang Y, Kwak JH, Lee K et al (2020) Isoflavones isolated from the seeds of Millettia ferruginea induced apoptotic cell death in human ovarian cancer cells. Molecules (Basel, Switzerland) 25(1):E207. https://doi.org/10.3390/molecules25010207

    Article  CAS  Google Scholar 

  38. Porter K, Fairlie WD, Laczka O et al (2020) Idronoxil as an anticancer agent: activity and mechanisms. Curr Cancer Drug Targets. https://doi.org/10.2174/1568009620666200102122830

    Article  PubMed  Google Scholar 

  39. Huang C, Hsu B, Wu N et al (2010) Anti-photoaging effects of soy isoflavone extract (aglycone and acetylglucoside form) from soybean cake. Int J Mol Sci 11(12):4782–4795. https://doi.org/10.3390/ijms11124782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bielecki A, Roberts J, Mehta R et al (2011) Estrogen receptor-β mediates the inhibition of DLD-1 human colon adenocarcinoma cells by soy isoflavones. Nutr Cancer 63(1):139–150. https://doi.org/10.1080/01635581.2010.516867

    Article  CAS  PubMed  Google Scholar 

  41. Lee EJ, Kim SY, Hyun JW et al (2010) Glycitein inhibits glioma cell invasion through down-regulation of MMP-3 and MMP-9 gene expression. Chem Biol Interact 185(1):18–24. https://doi.org/10.1016/j.cbi.2010.02.037

    Article  CAS  PubMed  Google Scholar 

  42. Harwood M, Danielewska-Nikiel B, Borzelleca JF et al (2007) A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45(11):2179–2205. https://doi.org/10.1016/j.fct.2007.05.015

    Article  CAS  PubMed  Google Scholar 

  43. Bischoff SC (2008) Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care 11(6):733–740. https://doi.org/10.1097/MCO.0b013e32831394b8

    Article  CAS  PubMed  Google Scholar 

  44. Hirpara KV, Aggarwal P, Mukherjee AJ et al (2009) Quercetin and its derivatives: synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability. Anti-cancer Agents Med Chem 9(2):138–161. https://doi.org/10.2174/187152009787313855

    Article  CAS  Google Scholar 

  45. Mutoh M, Takahashi M, Fukuda K et al (2000) Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure. Carcinogenesis 21(5):959–963. https://doi.org/10.1093/carcin/21.5.959

    Article  CAS  PubMed  Google Scholar 

  46. Srivastava NS, Srivastava RAK (2019) Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells. Phytomed Int J Phytother Phytopharmacol 52:117–128. https://doi.org/10.1016/j.phymed.2018.09.224

    Article  CAS  Google Scholar 

  47. Cruz-Correa M, Shoskes DA, Sanchez P et al (2006) Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 4(8):1035–1038. https://doi.org/10.1016/j.cgh.2006.03.020

    Article  CAS  PubMed  Google Scholar 

  48. Chuammitri P, Srikok S, Saipinta D et al (2017) The effects of quercetin on microRNA and inflammatory gene expression in lipopolysaccharide-stimulated bovine neutrophils. Vet World 10(4):403–410. https://doi.org/10.14202/vetworld.2017.403-410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu Y, Tang Z, Lin Y et al (2017) Effects of quercetin on proliferation and migration of human glioblastoma U251 cells. Biomed Pharmacother Biomed Pharmacother 92:33–38. https://doi.org/10.1016/j.biopha.2017.05.044

    Article  CAS  PubMed  Google Scholar 

  50. Olson ER, Melton T, Dickinson SE et al (2010) Quercetin potentiates UVB-induced c-Fos expression: implications for its use as a chemopreventive agent. Cancer Prev Res (Philadelphia, Pa.) 3(7):876–884. https://doi.org/10.1158/1940-6207.CAPR-09-022

    Article  CAS  Google Scholar 

  51. Ruiz PA, Braune A, Hölzlwimmer G et al (2007) Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr 137(5):1208–1215. https://doi.org/10.1093/jn/137.5.1208

    Article  CAS  PubMed  Google Scholar 

  52. Richter M, Ebermann R, Marian B (1999) Quercetin-induced apoptosis in colorectal tumor cells: possible role of EGF receptor signaling. Nutr Cancer 34(1):88–99. https://doi.org/10.1207/S15327914NC340113

    Article  CAS  PubMed  Google Scholar 

  53. Qi J, Yu J, Li Y et al (2019) Alternating consumption of β-glucan and quercetin reduces mortality in mice with colorectal cancer. Food Sci Nutr 7(10):3273–3285. https://doi.org/10.1002/fsn3.1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Granato M, Rizzello C, Gilardini Montani MS et al (2017) Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem 41:124–136. https://doi.org/10.1016/j.jnutbio.2016.12.011

    Article  CAS  PubMed  Google Scholar 

  55. Refolo MG, D'Alessandro R, Malerba N et al (2015) Anti proliferative and pro apoptotic effects of flavonoid quercetin are mediated by CB1 receptor in human colon cancer cell lines. J Cell Physiol 230(12):2973–2980. https://doi.org/10.1002/jcp.25026

    Article  CAS  PubMed  Google Scholar 

  56. Yang L, Liu Y, Wang M et al (2016) Quercetin-induced apoptosis of HT-29 colon cancer cells via inhibition of the Akt-CSN6-Myc signaling axis. Mol Med Rep 14(5):4559–4566. https://doi.org/10.3892/mmr.2016.5818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Samuel T, Fadlalla K, Mosley L et al (2012) Dual-mode interaction between quercetin and DNA-damaging drugs in cancer cells. Anticancer Res 32(1):61–71 (PMID:22213289)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, 510655, People’s Republic of China

    Yi Lu, Jiachen Sun, Minhui Hu, Xianhe Kong, Weijie Zhong & Chujun Li

  2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China

    Yi Lu, Jiachen Sun, Minhui Hu, Xianhe Kong, Weijie Zhong & Chujun Li

Authors
  1. Yi Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiachen Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minhui Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xianhe Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weijie Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chujun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chujun Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (RAR 5505 kb)

Supplementary file2 (DOCX 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, Y., Sun, J., Hu, M. et al. Network Pharmacology Analysis to Uncover the Potential Mechanisms of Lycium barbarum on Colorectal Cancer. Interdiscip Sci Comput Life Sci 12, 515–525 (2020). https://doi.org/10.1007/s12539-020-00397-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12539-020-00397-1

Keywords

Search

Navigation