Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2021

Open Access 01-12-2021 | Active Ingredients | Research article

A network pharmacology perspective for deciphering potential mechanisms of action of Solanum nigrum L. in bladder cancer

Authors: Yang Dong, Lin Hao, Kun Fang, Xiao-xiao Han, Hui Yu, Jian-jun Zhang, Long-jun Cai, Tao Fan, Wen-da Zhang, Kun Pang, Wei-ming Ma, Xi-tao Wang, Cong-hui Han

Published in: BMC Complementary Medicine and Therapies | Issue 1/2021

Login to get access

Abstract

Background

Solanum nigrum L. decoction has been used as a folklore medicine in China to prevent the postoperative recurrence of bladder cancer (BC). However, there are no previous pharmacological studies on the protective mechanisms of this activity of the plant. Thus, this study aimed to perform a systematic analysis and to predict the potential action mechanisms underlying S. nigrum activity in BC based on network pharmacology.

Methods

Based on network pharmacology, the active ingredients of S. nigrum and the corresponding targets were identified using the Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform database, and BC-related genes were screened using GeneCards and the Online Mendelian Inheritance in Man database. In addition, ingredient-target (I–T) and protein–protein interaction (PPI) networks were constructed using STRING and Cytoscape, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, and then the pathways directly related to BC were integrated manually to reveal the pharmacological mechanism underlying S. nigrum-medicated therapeutic effects in BC.

Results

Seven active herbal ingredients from 39 components of S. nigrum were identified, which shared 77 common target genes related to BC. I-T network analysis revealed that quercetin was associated with all targets and that NCOA2 was targeted by four ingredients. Besides, interleukin 6 had the highest degree value in the PPI network, indicating a hub role. A subsequent gene enrichment analysis yielded 86 significant GO terms and 89 significant pathways, implying that S. nigrum had therapeutic benefits in BC through multi-pathway effects, including the HIF-1, TNF, P53, MAPK, PI3K/Akt, apoptosis and bladder cancer pathway.

Conclusions

S. nigrum may mediate pharmacological effects in BC through multi-target and various signaling pathways. Further validation is required experimentally. Network pharmacology approach provides a predicative novel strategy to reveal the holistic mechanism of action of herbs.
Appendix
Available only for authorised users
Literature
1.
Feng RM, Zong YN, Cao SM, Xu RH. Current cancer situation in China: good or bad news from the 2018 global Cancer statistics? Cancer Commun. 2019;39(1):22.CrossRef
2.
Crijnen J, De Reijke TM. Emerging intravesical drugs for the treatment of non muscle-invasive bladder cancer. Expert Opin Emerg Drugs. 2018;23(2):135–47.CrossRefPubMed
3.
4.
Vale C. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data advanced bladder Cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):189–99 discussion 199–201.CrossRef
5.
Vale C. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–5 discussion 205–6.CrossRef
6.
Vashistha V, Quinn DI, Dorff TB, Daneshmand S. Current and recent clinical trials for perioperative systemic therapy for muscle invasive bladder cancer: a systematic review. BMC Cancer. 2014;14:966.PubMedCentralCrossRefPubMed
7.
Zehnder P, Studer UE, Skinner EC, Thalmann GN, Miranda G, Roth B, et al. Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades. BJU Int. 2013;112(2):E51–8.CrossRefPubMed
8.
Gakis G. Management of muscle-invasive bladder cancer in the 2020s: challenges and perspectives. Eur Urol Focus. 2020;6(4):632–8.CrossRefPubMed
9.
Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014;32(18):1895–901.PubMedCentralCrossRefPubMed
10.
Singh P, Black P. Emerging role of checkpoint inhibition in localized bladder cancer. Urol Oncol. 2016;34(12):548–55.CrossRefPubMed
11.
An L, Tang JT, Liu XM, Gao NN. Review about mechanisms of anti-cancer of Solanum nigrum. Zhongguo Zhong Yao Za Zhi. 2006;31(15):1225 –6, 1260.PubMed
12.
Huang HC, Syu KY, Lin JK. Chemical composition of Solanum nigrum Linn extract and induction of autophagy by leaf water extract and its major flavonoids in AU565 breast cancer cells. J Agric Food Chem. 2010;58(15):8699–708.CrossRefPubMed
13.
Nath LR, Gorantla JN, Thulasidasan AK, Vijayakurup V, Shah S, Anwer S, et al. Evaluation of uttroside B, a saponin from Solanum nigrum Linn, as a promising chemotherapeutic agent against hepatocellular carcinoma [sci. rep.:36318]. Sci Rep. 2016;6:36318.PubMedCentralCrossRefPubMed
14.
Son YO, Kim J, Lim JC, Chung Y, Chung GH, Lee JC. Ripe fruit of Solanum nigrum L. inhibits cell growth and induces apoptosis in MCF-7 cells. Food Chem Toxicol. 2003;41(10):1421–8.CrossRefPubMed
15.
Shen KH, Liao AC, Hung JH, Lee WJ, Hu KC, Lin PT, et al. Alpha-solanine inhibits invasion of human prostate cancer cell by suppressing epithelial-mesenchymal transition and MMPs expression. Molecules. 2014;19(8):11896–914.PubMedCentralCrossRefPubMed
16.
Wang HC, Wu DH, Chang YC, Li YJ, Wang CJ. Solanum nigrum Linn. Water extract inhibits metastasis in mouse melanoma cells in vitro and in vivo. J Agric Food Chem. 2010;58(22):11913–23.CrossRefPubMed
17.
Huang C, Zheng C, Li Y, Wang Y, Lu A, Yang L. Systems pharmacology in drug discovery and therapeutic insight for herbal medicines. Brief Bioinform. 2014;15(5):710–33.CrossRefPubMed
18.
19.
Chen G, Huang C, Liu Y, Chen T, Huang R, Liang M, et al. A network pharmacology approach to uncover the potential mechanism of Yinchensini decoction. Evid Based Complement Alternat Med. 2018;2018:2178610.PubMedCentralPubMedCrossRef
20.
Xu X, Zhang W, Huang C, Li Y, Yu H, Wang Y, et al. A novel chemometric method for the prediction of human oral bioavailability. Int J Mol Sci. 2012;13(6):6964–82.PubMedCentralCrossRefPubMed
21.
Tao W, Xu X, Wang X, Li B, Wang Y, Li Y, Yang L. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. J Ethnopharmacol. 2013;145(1):1–10.CrossRefPubMed
22.
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014;6:13.PubMedCentralCrossRefPubMed
23.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074–82.CrossRefPubMed
24.
Ye H, Ye L, Kang H, Zhang D, Tao L, Tang K, et al. HIT: linking herbal active ingredients to targets. Nucleic Acids Res. 2011;39((database issue)):D1055–9.CrossRefPubMed
25.
Yu H, Chen J, Xu X, Li Y, Zhao H, Fang Y, et al. A systematic prediction of multiple drug-target interactions from chemical, genomic, and pharmacological data. PLoS One. 2012;7(5):e37608.PubMedCentralCrossRefPubMed
26.
UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47(D1):D506–15.CrossRef
27.
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics. 2016;54(1):1.30.1–1.30.33.CrossRef
28.
Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online Mendelian Inheritance in Man (OMIM), a KnowledgeBase of human genes and genetic disorders. Nucleic Acids Res. 2005;33((database issue)):D514–7.PubMed
29.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.PubMedCentralCrossRefPubMed
30.
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–13.CrossRefPubMed
31.
The Gene Ontology Consortium. Expansion of the gene ontology KnowledgeBase and resources. Nucleic Acids Res. 2017;45(D1):D331–8.CrossRef
32.
Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–61.CrossRefPubMed
33.
34.
Yu G, Wang LG, Yan GR, He QY. DOSE: an R/bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics. 2015;31(4):608–9.CrossRefPubMed
35.
36.
37.
Ma L, Feugang JM, Konarski P, Wang J, Lu J, Fu S, et al. Growth inhibitory effects of quercetin on bladder cancer cell. Front Biosci. 2006;11:2275–85.CrossRefPubMed
38.
Su Q, Peng M, Zhang Y, Xu W, Darko KO, Tao T, et al. Quercetin induces bladder cancer cells apoptosis by activation of AMPK signaling pathway. Am J Cancer Res. 2016;6(2):498–508.PubMedCentralPubMed
39.
Chen F, Chen X, Yang D, Che X, Wang J, Li X, et al. Isoquercitrin inhibits bladder cancer progression in vivo and in vitro by regulating the PI3K/Akt and PKC signaling pathways. Oncol Rep. 2016;36(1):165–72.CrossRefPubMed
40.
Turner KA, Manouchehri JM, Kalafatis M. Sensitization of recombinant human tumor necrosis factor-related apoptosis-inducing ligand-resistant malignant melanomas by quercetin. Melanoma Res. 2018;28(4):277–85.PubMedCentralCrossRefPubMed
41.
Yang CS, Landau JM, Huang MT, Newmark HL. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr. 2001;21:381–406.CrossRefPubMed
42.
Di Lorenzo G, Pagliuca M, Perillo T, Zarrella A, Verde A, De Placido S, Buonerba C. Complete response and fatigue improvement with the combined use of cyclophosphamide and quercetin in a patient with metastatic bladder cancer: a case report. Medicine (Baltimore). 2016;95(5):e2598.CrossRef
43.
Cao ZQ, Wang XX, Lu L, Xu JW, Li XB, Zhang GR, et al. Beta-sitosterol and gemcitabine exhibit synergistic anti-pancreatic cancer activity by modulating apoptosis and inhibiting epithelial-mesenchymal transition by deactivating Akt/GSK-3beta signaling. Front Pharmacol. 2018;9:1525.CrossRefPubMed
44.
Yu H, Liu Y, Niu C, Cheng Y. Diosgenin increased DDX3 expression in hepatocellular carcinoma. Am J Transl Res. 2018;10(11):3590–9.PubMedCentralPubMed
45.
Dong J, Lei C, Lu D, Wang Y. Direct biotransformation of dioscin into diosgenin in rhizome of Dioscorea zingiberensis by Penicillium dioscin. Indian J Microbiol. 2015;55(2):200–6.CrossRefPubMed
46.
Meija L, Söderholm P, Samaletdin A, Ignace G, Siksna I, Joffe R, et al. Dietary intake and major sources of plant lignans in Latvian men and women. Int J Food Sci Nutr. 2013;64(5):535–43.CrossRefPubMed
47.
Lin Y, Wolk A, Håkansson N, Lagergren J, Lu Y. Dietary intake of lignans and risk of esophageal and gastric adenocarcinoma: a cohort study in Sweden. Cancer Epidemiol Biomark Prev. 2013;22(2):308–12.CrossRef
48.
Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey A, Harper P. Dietary phytoestrogen intake is associated with reduced colorectal cancer risk. J Nutr. 2006;136(12):3046–53.CrossRefPubMed
49.
Kim YS, Gong X, Rubin LP, Choi SW, Kim Y. Beta-carotene 15,15′-oxygenase inhibits cancer cell stemness and metastasis by regulating differentiation-related miRNAs in human neuroblastoma. J Nutr Biochem. 2019;69:31–43.CrossRefPubMed
50.
Casaburi I, Chimento A, De Luca A, Nocito M, Sculco S, Avena P, et al. Cholesterol as an endogenous ERRalpha agonist: a new perspective to cancer treatment. Front Endocrinol. 2018;9:525.CrossRef
51.
García ME, Borioni JL, Cavallaro V, Puiatti M, Pierini AB, Murray AP, Peñéñory AB. Solanocapsine derivatives as potential inhibitors of acetylcholinesterase: synthesis, molecular docking and biological studies. Steroids. 2015;104:95–110.CrossRefPubMed
52.
van Kessel KE, Zuiverloon TC, Alberts AR, Boormans JL, Zwarthoff EC. Targeted therapies in bladder cancer: an overview of in vivo research. Nat Rev Urol. 2015;12(12):681–94.CrossRefPubMed
53.
Mazzola CR, Chin J. Targeting the VEGF pathway in metastatic bladder cancer. Expert Opin Investig Drugs. 2015;24(7):913–27.CrossRefPubMed
54.
Breyer J, Wirtz RM, Laible M, Schlombs K, Erben P, Kriegmair MC, et al. ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC). Virchows Arch. 2016;469(5):547–52.CrossRefPubMed
55.
Kriegmair MC, Wirtz RM, Worst TS, Breyer J, Ritter M, Keck B, et al. Prognostic value of molecular breast cancer subtypes based on Her2, ESR1, PGR and Ki67 mRNA-expression in muscle invasive bladder cancer. Transl Oncol. 2018;11(2):467–76.PubMedCentralCrossRefPubMed
56.
Breyer J, Wirtz RM, Otto W, Laible M, Schlombs K, Erben P, et al. Predictive value of molecular subtyping in NMIBC by RT-qPCR of ERBB2, ESR1, PGR and MKI67 from formalin fixed TUR biopsies. Oncotarget. 2017;8(40):67684–95.PubMedCentralCrossRefPubMed
57.
Zhao Z, Zhang M, Duan X, Deng T, Qiu H, Zeng G. Low NR3C2 levels correlate with aggressive features and poor prognosis in non-distant metastatic clear-cell renal cell carcinoma. J Cell Physiol. 2018;233(10):6825–38.CrossRefPubMed
58.
Long MD, Campbell MJ. Pan-cancer analyses of the nuclear receptor superfamily. Nucl Recept Res. 2015;2:101182.CrossRef
59.
Vainer N, Dehlendorff C, Johansen JS. Systematic literature review of IL-6 as a biomarker or treatment target in patients with gastric, bile duct, pancreatic and colorectal cancer. Oncotarget. 2018;9(51):29820–41.PubMedCentralCrossRefPubMed
60.
Chen MF, Lin PY, Wu CF, Chen WC, Wu CT. IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS One. 2013;8(4):e61901.PubMedCentralCrossRefPubMed
61.
Zhao L, Wang L, Di SN, Xu Q, Ren QC, Chen SZ, et al. Steroidal alkaloid solanine a from Solanum nigrum Linn. Exhibits anti-inflammatory activity in lipopolysaccharide/interferon gamma-activated murine macrophages and animal models of inflammation. Biomed Pharmacother. 2018;105:606–15.CrossRefPubMed
62.
Clemente-Vicario F, Alvarez CE, Rowell JL, Roy S, London CA, Kisseberth WC, et al. Human genetic relevance and potent antitumor activity of heat shock protein 90 inhibition in canine lung adenocarcinoma cell lines. PLoS One. 2015;10(11):e0142007.PubMedCentralCrossRefPubMed
63.
64.
Shigeishi H, Sugiyama M, Tahara H, Ono S, Kumar Bhawal U, Okura M, et al. Increased telomerase activity and hTERT expression in human salivary gland carcinomas. Oncol Lett. 2011;2(5):845–50.PubMedCentralPubMed
65.
Chang L, Shi R, Yang T, Li F, Li G, Guo Y, et al. Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity. J Exp Clin Cancer Res. 2013;32:101.PubMedCentralCrossRefPubMed
66.
Soria F, Moschini M, Haitel A, Wirth GJ, Gust KM, Briganti A, et al. The effect of HER2 status on oncological outcomes of patients with invasive bladder cancer. Urol Oncol. 2016;34(12):533 e531–10.CrossRef
67.
Daga M, Pizzimenti S, Dianzani C, Cucci MA, Cavalli R, Grattarola M, et al. Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression. Phytomedicine. 2019;56:156–64.CrossRefPubMed
68.
Sun J, Zhang H, Tao D, Xie F, Liu F, Gu C, et al. CircCDYL inhibits the expression of C-MYC to suppress cell growth and migration in bladder cancer. Artif Cells Nanomed Biotechnol. 2019;47(1):1349–56.CrossRefPubMed
69.
Liu C, Tate T, Batourina E, Truschel ST, Potter S, Adam M, et al. Pparg promotes differentiation and regulates mitochondrial gene expression in bladder epithelial cells. Nat Commun. 2019;10(1):4589.PubMedCentralCrossRefPubMed
70.
Pinto-Leite R, Arantes-Rodrigues R, Sousa N, Oliveira PA, Santos L. mTOR inhibitors in urinary bladder cancer. Tumour Biol. 2016;37(9):11541–51.CrossRefPubMed
71.
Riese DJ, Cullum RL. Epiregulin: roles in normal physiology and cancer. Semin Cell Dev Biol. 2014;28:49–56.CrossRefPubMed
72.
Ceci C, Lacal PM, Tentori L, De Martino M, Miano R, Graziani G. Experimental evidence of the antitumor, antimetastatic and antiangiogenic activity of ellagic acid. Nutrients. 2018;10(11):1756.PubMedCentralCrossRef
73.
74.
Mukherjee N, Houston TJ, Cardenas E, Ghosh R. To be an ally or an adversary in bladder cancer: the NF-κB story has not unfolded. Carcinogenesis. 2015;36(3):299–306.CrossRefPubMed
75.
Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W. Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem J. 2005;392(2):249–61.PubMedCentralCrossRefPubMed
76.
Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15(1):25–41.CrossRefPubMed
77.
Pan B, Zhong W, Deng Z, Lai C, Chu J, Jiao G, et al. Inhibition of prostate cancer growth by solanine requires the suppression of cell cycle proteins and the activation of ROS/P38 signaling pathway. Cancer Med. 2016;5(11):3214–22.PubMedCentralCrossRefPubMed
78.
Li J, Li Q, Feng T, Zhang T, Li K, Zhao R, et al. Antitumor activity of crude polysaccharides isolated from Solanum nigrum Linne on U14 cervical carcinoma bearing mice. Phytother Res. 2007;21(9):832–40.CrossRefPubMed
79.
Streeter EH, Harris AL. Angiogenesis in bladder cancer - prognostic marker and target for future therapy. Surg Oncol. 2002;11(1–2):85–100.CrossRefPubMed
80.
Jain R, Sharma A, Gupta S, Sarethy IP, Gabrani R. Solanum nigrum: current perspectives on therapeutic properties. Altern Med Rev. 2011;16(1):78–85.PubMed
81.
Oh SS, Choi MW, Choi MR, Lee JH, Yang HJ, Choi YJ, et al. Acute interstitial nephritis induced by Solanum nigrum. Kidney Res Clin Pract. 2016;35(4):252–4.PubMedCentralCrossRefPubMed
Metadata
Title
A network pharmacology perspective for deciphering potential mechanisms of action of Solanum nigrum L. in bladder cancer
Authors
Yang Dong
Lin Hao
Kun Fang
Xiao-xiao Han
Hui Yu
Jian-jun Zhang
Long-jun Cai
Tao Fan
Wen-da Zhang
Kun Pang
Wei-ming Ma
Xi-tao Wang
Cong-hui Han
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2021
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-021-03215-3

Other articles of this Issue 1/2021

BMC Complementary Medicine and Therapies 1/2021 Go to the issue

Research article

1H nuclear magnetic resonance-based metabolite profiling of guava leaf extract: an attempt to develop a prototype for standardization of plant extracts

Research article

Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats

Research article

Biological evaluation of Safrole oil and Safrole oil Nanoemulgel as antioxidant, antidiabetic, antibacterial, antifungal and anticancer

Research

Antiproliferative, antibacterial, and antioxidant activities of Bauhinia strychnifolia Craib aqueous extracts in gut and liver perspective

Retraction Note

Retraction Note: Antimalarial efficacy of Pongamia pinnata (L) Pierre against Plasmodium falciparum (3D7 strain) and Plasmodium berghei (ANKA)

Correction

Correction to: Chemical composition of essential oils of eight Tunisian Eucalyptus species and their antibacterial activity against strains responsible for otitis