Skip to main content

Advertisement

SpringerLink
Log in

Identification of novel inhibitors from Urtica spp against TNBC targeting JAK2 receptor for breast cancer therapy

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

Abstract

Breast cancer is the most prevalent form of cancer in women globally, and TNBC (triple-negative breast cancer) is its aggressive type since it lacks the usual targets. JAK2/STAT3 pathway can be an important lead in anticancer drug discovery, as restraining the downstream signalling of this pathway results in the induction of cell apoptosis. Moreover, various limitations associated with chemotherapy are the reason to find an alternative herbal-based therapy. For this study, we collected Urtica dioica and U. parviflora from different regions of Uttarakhand, followed by preparation of their leaf and stem extracts in different solvents. The GC–MS analysis of these extracts revealed a total of 175 compounds to be present in them. Further, by molecular docking approach, we studied the interaction between these compounds and JAK2, and 12 major compounds with better binding energy than the control Paclitaxel were identified. In addition, the selected hits were also reported to display better pharmacokinetic properties. Moreover, extracts from both the Urtica spp. displayed significant anticancer activity against MDA-MB-231(TNBC cell line) and exhibited lower cytotoxicity in healthy cell lines, i.e. HEK293T, indicating that these extracts were safer to use. Hence, the findings in our study can be crucial in the area of herbal-based target-specific drug development against breast cancer.

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

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Rajabi S, Maresca M, Yumashev AV, Choopani R, Hajimehdipoor H. The Most competent plant-derived natural products for targeting apoptosis in cancer therapy. Biomolecules. 2021. https://doi.org/10.3390/BIOM11040534.

    Article  PubMed  PubMed Central  Google Scholar 

  2. https://www.who.int/news-room/fact-sheets/detail/cancer.

  3. Sun S, Zhao Y, Xu K. Post-adjuvant chemotherapy for triple-negative breast cancer. Med Hypotheses. 2016;90:74–5. https://doi.org/10.1016/J.MEHY.2016.03.009.

    Article  PubMed  Google Scholar 

  4. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48. https://doi.org/10.1056/NEJMRA1001389.

    Article  CAS  PubMed  Google Scholar 

  5. Bakar AA, Akhtar MN, Ali NM, Yeap SK, Quah CK, Loh WS, Alitheen NB, Zareen S, Ul-Haq Z, Shah SAA. Design, synthesis and docking studies of Flavokawain B type Chalcones and their cytotoxic effects on MCF-7 and MDA-MB-231 cell lines. Molecules. 2018. https://doi.org/10.3390/MOLECULES23030616.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kiu H, Nicholson SE. Biology and significance of the JAK/STAT signalling pathways. Growth Factors. 2012;30:88–106. https://doi.org/10.3109/08977194.2012.660936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wu H, Huang M, Cao P, Wang T, Shu Y, Liu P. MiR-135a targets JAK2 and inhibits gastric cancer cell proliferation. Cancer Biol Ther. 2012;13:281–8. https://doi.org/10.4161/CBT.18943.

    Article  CAS  PubMed  Google Scholar 

  8. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A, Jove R. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 2001;20:2499–513. https://doi.org/10.1038/SJ.ONC.1204349.

    Article  CAS  PubMed  Google Scholar 

  9. Marotta LLC, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gönen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24− stem cell-like breast cancer cells in human tumors. J Clin Invest. 2011;121:2723–35. https://doi.org/10.1172/JCI44745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim MS, Lee WS, Jeong J, Kim SJ, Jin W. Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer. Oncotarget. 2015;6:40158–71. https://doi.org/10.18632/ONCOTARGET.5522.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nakamura H, Maeda H. Cancer chemotherapy, fundamentals of pharmaceutical. Nanoscience. 2023. https://doi.org/10.1007/978-1-4614-9164-4_15.

    Article  Google Scholar 

  12. Dehelean CA, Marcovici I, Soica C, Mioc M, Coricovac D, Iurciuc S, Cretu OM, Pinzaru I. Plant-derived anticancer compounds as new perspectives in drug discovery and alternative therapy. Molecules. 2021. https://doi.org/10.3390/MOLECULES26041109.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Iqbal J, Abbasi BA, Mahmood T, Kanwal S, Ali B, Shah SA, Khalil AT. Plant-derived anticancer agents: A green anticancer approach, Asian Pac. J Trop Biomed. 2017;7:1129–50. https://doi.org/10.1016/J.APJTB.2017.10.016.

    Article  Google Scholar 

  14. Orhan IE, Senol Deniz FS. Natural products as potential leads against coronaviruses: could they be encouraging structural models against SARS-CoV-2? Nat Prod Bioprospect. 2020;10:171–86. https://doi.org/10.1007/S13659-020-00250-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kregiel D, Pawlikowska E, Antolak H. Urtica spp.: Ordinary plants with extraordinary properties, molecules : a journal of synthetic chemistry and natural product. Chemistry. 2018. https://doi.org/10.3390/MOLECULES23071664.

    Article  Google Scholar 

  16. Upreti S, Prusty JS, Pandey SC, Kumar A, Samant M. Identification of novel inhibitors of angiotensin-converting enzyme 2 (ACE-2) receptor from Urtica dioica to combat coronavirus disease 2019 (COVID-19). Mol Divers. 2021;25:1795. https://doi.org/10.1007/S11030-020-10159-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Upreti S, Prusty JS, Kumar A, Samant M. Identification of SARS-CoV-2 spike protein inhibitors from urtica dioica to develop herbal-based therapeutics against COVID-19, World. J Tradit Chin Med. 2023;9:61–70. https://doi.org/10.4103/2311-8571.358784.

    Article  CAS  Google Scholar 

  18. Tao Y, Zou W, Nanayakkara S, Kraka E. PyVibMS: a PyMOL plugin for visualizing vibrations in molecules and solids. J Mol Model. 2020. https://doi.org/10.1007/S00894-020-04508-Z.

    Article  PubMed  Google Scholar 

  19. Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015;1263:243–50. https://doi.org/10.1007/978-1-4939-2269-7_19.

    Article  CAS  PubMed  Google Scholar 

  20. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1:337–41. https://doi.org/10.1016/J.DDTEC.2004.11.007.

    Article  CAS  PubMed  Google Scholar 

  21. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:1–13. https://doi.org/10.1038/srep42717.

    Article  Google Scholar 

  22. Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018;46:W257–63. https://doi.org/10.1093/NAR/GKY318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 2015;58:4066–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chandra Pandey S, Dhami DS, Jha A, Chandra Shah G, Kumar A, Samant M. Identification of trans-2-cis-8-Matricaria-ester from the essential oil of erigeron multiradiatus and evaluation of its antileishmanial potential by in vitro and in silico approaches. ACS Omega. 2019;4:14640–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hu K, Law JH, Fotovati A, Dunn SE. Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumor-initiating cells. Breast Cancer Res. 2012;14:R22. https://doi.org/10.1186/BCR3107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ayele TM, Muche ZT, Teklemariam AB, Kassie AB, Abebe EC. Role of JAK2/STAT3 signaling pathway in the tumorigenesis, chemotherapy resistance, and treatment of solid tumors: a systemic review. J Inflamm Res. 2022;15:1349. https://doi.org/10.2147/JIR.S353489.

    Article  Google Scholar 

  27. Argetsinger LS, Kouadio J-LK, Steen H, Stensballe A, Jensen ON, Carter-Su C. Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol Cell Biol. 2004;24:4955–67. https://doi.org/10.1128/MCB.24.11.4955-4967.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178:2623–9. https://doi.org/10.4049/JIMMUNOL.178.5.2623.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are thankful to the Department of Zoology, SSJ University, Almora (Uttarakhand), India, and School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Patia, India, for providing the facility for this work.

Funding

This work is supported by the DST-FIST grant SR/FST/LS- I/2018/131 to the Department of Zoology.

Author information

Authors and Affiliations

  1. Cell and Molecular Biology Laboratory, Department of Zoology, Soban Singh Jeena University Campus, Almora, Uttarakhand, India

    Shobha Upreti & Mukesh Samant

  2. Department of Zoology, Kumaun University, Nainital, Uttarakhand, India

    Shobha Upreti

  3. School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Patia, Bhubaneswar, 751024, Odisha, India

    Kartik Muduli, Jagannath Pradhan & Selvakumar Elangovan

Authors
  1. Shobha Upreti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kartik Muduli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jagannath Pradhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Selvakumar Elangovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mukesh Samant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mukesh Samant.

Ethics declarations

Conflict of interest

The authors have declared no conflict 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

Upreti, S., Muduli, K., Pradhan, J. et al. Identification of novel inhibitors from Urtica spp against TNBC targeting JAK2 receptor for breast cancer therapy. Med Oncol 40, 326 (2023). https://doi.org/10.1007/s12032-023-02193-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-023-02193-5

Keywords

Search

Navigation