Skip to main content
SpringerLink
Log in

Identification of the therapeutic mechanism of the saffron crocus on glioma through network pharmacology and bioinformatics analysis

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Saffron crocus is a herbal medicine of traditional Tibetan medicine (TTM). Saffron extract has been indicated to inhibit tumor cell growth and promote tumor cell apoptosis in a variety of cancers, including glioma, but the specific mechanism is not clear. To study the possible mechanism of saffron action on glioma, network pharmacology and bioinformatics analysis methods were used in this study. We used the online database to obtain the active ingredients of saffron and their targets. Glioma-related targets were also acquired from online database. We intersected drug targets with glioma-related targets and conducted PPI network analysis to obtain network core genes. Then, we obtained RNA-seq data from The Cancer Genome Atlas (TCGA) database for glioma patients. Through different expression analysis and lasso regression, further screening of core genes in the network was conducted, and a prognostic model was established. The sample was divided into two groups with high and low risk using this model. The RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) database were used to further validate our prediction model. Then, we explored the difference in pathways enrichment between high-risk patients and low-risk patients and calculated the difference in immune microenvironment between the two groups. Finally, we used scRNA-seq data in the CGGA database to analyze the cell types in which the model gene is mainly enriched and predicted the cell types which saffron effected on.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Data availability

All data involved in this study were downloaded from public databases such as TCGA and CGGA. The patients involved in the database have obtained ethical approval. Users can download relevant data for free for research and publish relevant articles. Our study is based on open source data, so there are no ethical issues and other conflict of interest.

Abbreviations

GBM:

Glioblastoma multiforme

TCGA:

The Cancer Genome Atlas

CGGA:

Chinese Glioma Genome Atlas

PCA:

Principal component analysis

TSNE:

T-distributed stochastic neighbor embedding

UMAP:

Uniform manifold approximation and approximation projection

ROC:

Receiver operating characteristic curve

AUC:

Area under the curve

GSEA:

Gene set enrichment analysis

TIME:

Tumor immune microenvironment

PC:

Principal components

BE:

Binding energy

TTM:

Traditional Tibetan medicine

TCMSP:

Traditional Chinese Medicine Systems Pharmacology Database

OMIM:

Online Mendelian Inheritance in Man

GO:

Gene ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

GBM:

Glioblastoma

OB:

Oral bioavailability

DL:

Drug-likeness

PPI Network:

Protein–protein interaction network

PDB:

Protein data bank

BP:

Biological process

CC:

Cellular component

MF:

Molecular function

References

  1. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 2014;16:896–913. https://doi.org/10.1093/neuonc/nou087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18:170–86. https://doi.org/10.1038/s41571-020-00447-z.

    Article  PubMed  Google Scholar 

  3. Shergalis A, Bankhead A 3rd, Luesakul U, Muangsin N, Neamati N. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev. 2018;70:412–45. https://doi.org/10.1124/pr.117.014944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sousa-Pimenta M, Estevinho LM, Szopa A, Basit M, Khan K, Armaghan M, et al. Chemotherapeutic properties and side-effects associated with the clinical practice of terpene alkaloids: paclitaxel, docetaxel, and cabazitaxel. Front Pharmacol. 2023;14:1157306. https://doi.org/10.3389/fphar.2023.1157306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kwon YJ, Seo EB, Kim SK, Lee HS, Lee H, Jang YA, et al. Pharmacological anti-tumor effects of natural Chamaecyparis obtusa (siebold & zucc.) endl. Leaf extracts on breast cancer. J Ethnopharmacol. 2023;313:116598. https://doi.org/10.1016/j.jep.2023.116598.

    Article  CAS  PubMed  Google Scholar 

  6. Cordier W, Steenkamp P, Steenkamp V. Cytostatic and cytotoxic effects of a hot water and methanol extract of Acokanthera oppositifolia in HepG2 hepatocarcinoma cells. J Ethnopharmacol. 2023;314:116617. https://doi.org/10.1016/j.jep.2023.116617.

    Article  CAS  PubMed  Google Scholar 

  7. Chang H, Hou J, Shao Y, Xu M, Weng X, Du Y, et al. Sanggenon C inhibits cell proliferation and induces apoptosis by regulating the MIB1/DAPK1 axis in glioblastoma. MedComm. 2023;4:e281. https://doi.org/10.1002/mco2.281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hasan Abdali M, Afshar S, Sedighi Pashaki A, Dastan D, Gholami MH, Mahmoudi R, et al. Investigating the effect of radiosensitizer for ursolic acid and kamolonol acetate on HCT-116 cell line. Bioorg Med Chem. 2020;28:115152. https://doi.org/10.1016/j.bmc.2019.115152.

    Article  CAS  PubMed  Google Scholar 

  9. Nazari ZE, Iranshahi M. Biologically active sesquiterpene coumarins from Ferula species. Phytother Res. 2011;25:315–23. https://doi.org/10.1002/ptr.3311.

    Article  CAS  PubMed  Google Scholar 

  10. Kim TW, Lee HG. 6-Shogaol overcomes gefitinib resistance via ER stress in ovarian cancer cells. Int J Mol Sci. 2023;24:2639. https://doi.org/10.3390/ijms24032639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kantapan J, Dechsupa N, Tippanya D, Nobnop W, Chitapanarux I. Gallotannin from Bouea macrophylla seed extract suppresses cancer stem-like cells and radiosensitizes head and neck cancer. Int J Mol Sci. 2021;22:9253. https://doi.org/10.3390/ijms22179253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bauer-Wu S, Lhundup T, Tidwell T, Lhadon T, Ozawa-de Silva C, Dolma J, et al. Tibetan medicine for cancer: an overview and review of case studies. Integr Cancer Ther. 2014;13:502–12. https://doi.org/10.1177/1534735414549624.

    Article  PubMed  Google Scholar 

  13. Tang C, Zhao CC, Yi H, Geng ZJ, Wu XY, Zhang Y, et al. Traditional Tibetan medicine in cancer therapy by targeting apoptosis pathways. Front Pharmacol. 2020;11:976. https://doi.org/10.3389/fphar.2020.00976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Harrington M. Saffron offers protection from liver cancer. Lab Anim (NY). 2011;40:289. https://doi.org/10.1038/laban1011-289a.

    Article  PubMed  Google Scholar 

  15. Amin A, Hamza AA, Bajbouj K, Ashraf SS, Daoud S. Saffron: a potential candidate for a novel anticancer drug against hepatocellular carcinoma. Hepatology. 2011;54:857–67. https://doi.org/10.1002/hep.24433.

    Article  CAS  PubMed  Google Scholar 

  16. Amin A, Farrukh A, Murali C, Soleimani A, Praz F, Graziani G, et al. Saffron and its major ingredients’ effect on colon cancer cells with mismatch repair deficiency and microsatellite instability. Molecules. 2021;26:3855. https://doi.org/10.3390/molecules26133855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ege B, Yumrutas O, Ege M, Pehlivan M, Bozgeyik I. Pharmacological properties and therapeutic potential of saffron (Crocus sativus L.) in osteosarcoma. J Pharm Pharmacol. 2020;72:56–67. https://doi.org/10.1111/jphp.13179.

    Article  CAS  PubMed  Google Scholar 

  18. Moradzadeh M, Kalani MR, Avan A. The antileukemic effects of saffron (Crocus sativus L.) and its related molecular targets: a mini review. J Cell Biochem. 2019;120:4732–8. https://doi.org/10.1002/jcb.27525.

    Article  CAS  PubMed  Google Scholar 

  19. Bhandari PR. Crocus sativus L. (saffron) for cancer chemoprevention: a mini review. J Tradit Complement Med. 2015;5:81–7. https://doi.org/10.1016/j.jtcme.2014.10.009.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lambrianidou A, Koutsougianni F, Papapostolou I, Dimas K. Recent advances on the anticancer properties of saffron (Crocus sativus L.) and its major constituents. Molecules. 2020;26:86. https://doi.org/10.3390/molecules26010086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tavakkol-Afshari J, Brook A, Mousavi SH. Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Food Chem Toxicol. 2008;46:3443–7. https://doi.org/10.1016/j.fct.2008.08.018.

    Article  CAS  PubMed  Google Scholar 

  22. Naeimi M, Shafiee M, Kermanshahi F, Khorasanchi Z, Khazaei M, Ryzhikov M, et al. Saffron (Crocus sativus) in the treatment of gastrointestinal cancers: current findings and potential mechanisms of action. J Cell Biochem. 2019;120:16330–9. https://doi.org/10.1002/jcb.29126.

    Article  CAS  PubMed  Google Scholar 

  23. Das I, Das S, Saha T. Saffron suppresses oxidative stress in DMBA-induced skin carcinoma: a histopathological study. Acta Histochem. 2010;112:317–27. https://doi.org/10.1016/j.acthis.2009.02.003.

    Article  PubMed  Google Scholar 

  24. Zheng J, Zhou Y, Li Y, Xu DP, Li S, Li HB. Spices for prevention and treatment of cancers. Nutrients. 2016;8:495. https://doi.org/10.3390/nu8080495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nezamdoost Z, Saghebjoo M, Hoshyar R, Hedayati M, Keska A. High-intensity training and saffron: effects on breast cancer-related gene expression. Med Sci Sports Exerc. 2020;52:1470–6. https://doi.org/10.1249/MSS.0000000000002274.

    Article  CAS  PubMed  Google Scholar 

  26. Baba SA, Vahedi M, Ahmad I, Rajab BS, Babalghith AO, Irfan S, et al. Crocus sativus L. tepal extract induces apoptosis in human U87 glioblastoma cells. Biomed Res Int. 2022;2022:4740246. https://doi.org/10.1155/2022/4740246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Giakoumettis D, Pourzitaki C, Vavilis T, Tsingotjidou A, Kyriakoudi A, Tsimidou M, et al. Crocus sativus L. causes a non apoptotic calpain dependent death in C6 rat glioma cells, exhibiting a synergistic effect with temozolomide. Nutr Cancer. 2019;71:491–507. https://doi.org/10.1080/01635581.2018.1506493.

    Article  CAS  PubMed  Google Scholar 

  28. Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt H. Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci. 2022;43:136–50. https://doi.org/10.1016/j.tips.2021.11.004.

    Article  CAS  PubMed  Google Scholar 

  29. Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12:56–68. https://doi.org/10.1038/nrg2918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tang Y, Li M, Wang J, Pan Y, Wu FX. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems. 2015;127:67–72. https://doi.org/10.1016/j.biosystems.2014.11.005.

    Article  CAS  PubMed  Google Scholar 

  31. Colapietro A, Mancini A, Vitale F, Martellucci S, Angelucci A, Llorens S, et al. Crocetin extracted from saffron shows antitumor effects in models of human glioblastoma. Int J Mol Sci. 2020;21:423. https://doi.org/10.3390/ijms21020423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen S, Ma J, Yang L, Teng M, Lai ZQ, Chen X, et al. Anti-glioblastoma activity of kaempferol via programmed cell death induction: involvement of autophagy and pyroptosis. Front Bioeng Biotechnol. 2020;8:614419. https://doi.org/10.3389/fbioe.2020.614419.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kim EJ, Choi CH, Park JY, Kang SK, Kim YK. Underlying mechanism of quercetin-induced cell death in human glioma cells. Neurochem Res. 2008;33:971–9. https://doi.org/10.1007/s11064-007-9416-8.

    Article  CAS  PubMed  Google Scholar 

  34. Pan HC, Jiang Q, Yu Y, Mei JP, Cui YK, Zhao WJ. Quercetin promotes cell apoptosis and inhibits the expression of MMP-9 and fibronectin via the AKT and ERK signalling pathways in human glioma cells. Neurochem Int. 2015;80:60–71. https://doi.org/10.1016/j.neuint.2014.12.001.

    Article  CAS  PubMed  Google Scholar 

  35. Cai F, Zhang Y, Li J, Huang S, Gao R. Isorhamnetin inhibited the proliferation and metastasis of androgen-independent prostate cancer cells by targeting the mitochondrion-dependent intrinsic apoptotic and PI3K/Akt/mTOR pathway. 2020. Biosci Rep. https://doi.org/10.1042/BSR20192826.

  36. Li C, Li J, Li Y, Li L, Luo Y, Li J, et al. Isorhamnetin promotes MKN-45 gastric cancer cell apoptosis by inhibiting PI3K-mediated adaptive autophagy in a hypoxic environment. J Agric Food Chem. 2021;69:8130–43. https://doi.org/10.1021/acs.jafc.1c02620.

    Article  CAS  PubMed  Google Scholar 

  37. Wang JL, Quan Q, Ji R, Guo XY, Zhang JM, Li X, et al. Isorhamnetin suppresses PANC-1 pancreatic cancer cell proliferation through S phase arrest. Biomed Pharmacother. 2018;108:925–33. https://doi.org/10.1016/j.biopha.2018.09.105.

    Article  CAS  PubMed  Google Scholar 

  38. Hernandez Borrero LJ, El-Deiry WS. Tumor suppressor p53: biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer. 2021;1876:188556. https://doi.org/10.1016/j.bbcan.2021.188556.

    Article  CAS  PubMed  Google Scholar 

  39. Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 is a promising therapeutic target for hepatocellular carcinoma. Front Oncol. 2021;11:760971. https://doi.org/10.3389/fonc.2021.760971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yadav P, Yadav R, Jain S, Vaidya A. Caspase-3: a primary target for natural and synthetic compounds for cancer therapy. Chem Biol Drug Des. 2021;98:144–65. https://doi.org/10.1111/cbdd.13860.

    Article  CAS  PubMed  Google Scholar 

  41. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, Metabolism, and cancer. Cancer Discov. 2015;5:1024–39. https://doi.org/10.1158/2159-8290.CD-15-0507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li Y, Yu Y, Zhang Y, Zhou Y, Li C, Zhu J, et al. MAFIP is a tumor suppressor in cervical cancer that inhibits activation of the nuclear factor-kappa B pathway. Cancer Sci. 2011;102:2043–50. https://doi.org/10.1111/j.1349-7006.2011.02061.x.

    Article  CAS  PubMed  Google Scholar 

  43. Bredel M, Scholtens DM, Yadav AK, Alvarez AA, Renfrow JJ, Chandler JP, et al. NFKBIA deletion in glioblastomas. N Engl J Med. 2011;364:627–37. https://doi.org/10.1056/NEJMoa1006312.

    Article  CAS  PubMed  Google Scholar 

  44. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2:725–34. https://doi.org/10.1038/nri910.

    Article  CAS  PubMed  Google Scholar 

  45. Pavitra E, Kancharla J, Gupta VK, Prasad K, Sung JY, Kim J, et al. The role of NF-kappaB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy. Biomed Pharmacother. 2023;163:114822. https://doi.org/10.1016/j.biopha.2023.114822.

    Article  CAS  PubMed  Google Scholar 

  46. Xiao L, Lan X, Shi X, Zhao K, Wang D, Wang X, et al. Cytoplasmic RAP1 mediates cisplatin resistance of non-small cell lung cancer. Cell Death Dis. 2017;8:e2803. https://doi.org/10.1038/cddis.2017.210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE. NF-kappaB targeting for overcoming tumor resistance and normal tissues toxicity. J Cell Physiol. 2019;234:17187–204. https://doi.org/10.1002/jcp.28504.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Department of Science and Technology of Shandong Province (2020CXGC010903 and ZR2019ZD33), the Clinical Research Center of Shandong University (2020SDUCRCB002), and Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022003A).

Author information

Author notes

  1. Peng Zhao and Xingang Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, China

    Xiaobing Yang, Peng Zhao & Xingang Li

  2. Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China

    Xiaobing Yang, Peng Zhao & Xingang Li

  3. Department of Neurosurgery, International Mongolia Hospital of Inner Mongolia, Hohhot, China

    Dulegeqi Man

Authors
  1. Xiaobing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dulegeqi Man
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xingang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peng Zhao or Xingang Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, X., Man, D., Zhao, P. et al. Identification of the therapeutic mechanism of the saffron crocus on glioma through network pharmacology and bioinformatics analysis. Med Oncol 40, 296 (2023). https://doi.org/10.1007/s12032-023-02142-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-023-02142-2

Keywords

Search

Navigation