Skip to main content

Advertisement

SpringerLink
Log in

Harmaline exerts potentially anti-cancer effects on U-87 human malignant glioblastoma cells in vitro

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Harmaline is a β-carboline alkaloid that can be extracted from the seeds of Peganum harmala. Harmaline has been shown to exhibit a potent cytotoxic effect against tumor cells. In this study, the anti-glioblastoma activity of harmaline was investigated in vitro.

Methods and results

Cell viability, apoptosis, and cell cycle arrest were assessed in U-87 cells treated with harmaline at different doses. Reactive oxygen species (ROS) generation and the mRNA expression of apoptosis-associated genes were assessed. The anti-metastatic effect of harmaline on U-87 cells was evaluated by gelatin zymography assay where matrix metalloproteinase [MMP]-2/-9 enzymatic activity was measured, and the scratch assay was used to assess migratory responses. Flow cytometry demonstrated that harmaline could suppress the proliferation and induce sub-G1 cell cycle arrest and apoptotic cell death in glioblastoma cells. Harmaline treatment was also associated with an upregulation of the cell cycle-related genes, p21 and p53, and pro-apoptotic Bax, as well as the induction of ROS. The zymography assay indicated that the essential steps of metastasis were potently suppressed by harmaline through inhibiting the expression of MMP-2 and − 9. In addition, the migration of U-87 cells was significantly reduced after harmaline treatment.

Conclusion

Our data suggest a basis for further research of harmaline which has potential cytotoxic activities in glioblastoma cells; inducing cell cycle arrest and apoptosis, repression of migration, possibly invasion, and metastasis.

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

Data Availability

The data supporting findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Tavana E et al (2020) Quercetin: a promising phytochemical for the treatment of glioblastoma multiforme. BioFactors 46(3):356–366

    Article  CAS  PubMed  Google Scholar 

  2. Fisher JP, Adamson DC (2021) Current FDA-Approved therapies for High-Grade Malignant Gliomas. Biomedicines 9(3):324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Seraj QM (2022) Thymol has anticancer effects in U-87 human malignant glioblastoma cells. Mol Bio Rep

  4. Khan FA et al (2013) Recent pharmacological developments in β-carboline alkaloid “harmaline”. Eur J Pharmacol 721(1):391–394

    Article  CAS  PubMed  Google Scholar 

  5. Rashidi M et al (2022) Harmaline downregulates angiogenesis markers and suppresses the growth of 4T1 breast cancer cells in vivo and in vitro. Chemico-Biol Interact 365:110087

    Article  CAS  Google Scholar 

  6. β-Carboline Alkaloids: Biochemical and Pharmacological Functions Current Medicinal Chemistry, 2007. 14(4):479–500

  7. Hilber P, Chapillon P (2005) Effects of harmaline on anxiety-related behavior in mice. Physiol Behav 86(1–2):164–167

    Article  CAS  PubMed  Google Scholar 

  8. Lamchouri F et al (2013) Cytotoxicity of alkaloids isolated from Peganum harmala seeds. Pak J Pharm Sci 26(4):699–706

    CAS  PubMed  Google Scholar 

  9. Douer D (2002) New advances in the treatment of acute promyelocytic leukemia. Int J Hematol 76(Suppl 2):179–187

    Article  PubMed  Google Scholar 

  10. Zaker F, Oody A, Arjmand A (2007) A study on the antitumoral and differentiation effects of peganum harmala derivatives in combination with atra on leukaemic cells. Arch Pharm Res 30(7):844–849

    Article  CAS  PubMed  Google Scholar 

  11. Lamchouri F et al (2000) In vitro cell-toxicity of Peganum harmala alkaloids on cancerous cell-lines. Fitoterapia 71(1):50–54

    Article  CAS  PubMed  Google Scholar 

  12. Luo X-J, Peng J, Li Y-J (2011) Recent advances in the study on capsaicinoids and capsinoids. Eur J Pharmacol 650(1):1–7

    Article  CAS  PubMed  Google Scholar 

  13. Arshad N et al (2008) Peganum harmala can minimize Escherichia coli infection in Poultry, but Long-Term Feeding May Induce Side Effects. Poult Sci 87(2):240–249

    Article  CAS  PubMed  Google Scholar 

  14. Astulla A et al (2008) Alkaloids from the seeds of Peganum harmala showing antiplasmodial and vasorelaxant activities. J Nat Med 62(4):470–472

    Article  CAS  PubMed  Google Scholar 

  15. Wang Y et al (2015) Novel mechanism of harmaline on inducing G2/M cell cycle arrest and apoptosis by up-regulating Fas/FasL in SGC-7901 cells. Sci Rep 5:18613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hashemi S, Shabani S et al (2015) Peganum harmala L.’s anti-growth effect on a breast cancer cell line. Biotechnol Rep 8:138–143

    Article  Google Scholar 

  17. Xu B et al (2018) Effects of harmaline on cell growth of human liver cancer through the p53/p21 and Fas/FasL signaling pathways. Oncol Lett 15(2):1931–1936

    PubMed  Google Scholar 

  18. Jalili-Nik M et al (2020) Zerumbone Promotes Cytotoxicity in Human Malignant Glioblastoma Cells through Reactive Oxygen Species (ROS) Generation Oxid Med Cell Longev, 2020. 3237983

  19. Sato H et al (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370(6484):61–65

    Article  CAS  PubMed  Google Scholar 

  20. Afshari AR et al (2020) Modulation of Calcium Signaling in Glioblastoma Multiforme: A Therapeutic Promise for Natural Products. Mini Rev Med Chem 20(18):1879–1899

    Article  CAS  PubMed  Google Scholar 

  21. Foroutan Z et al (2022) Plant-based synthesis of cerium oxide nanoparticles as a drug delivery system in improving the anticancer effects of free temozolomide in glioblastoma (U87) cells. Ceram Int 48(20):30441–30450

    Article  CAS  Google Scholar 

  22. Roy S et al (2020) Discovery of Harmaline as a potent inhibitor of Sphingosine Kinase-1: a Chemopreventive Role in Lung Cancer. ACS Omega 5(34):21550–21560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schedle A et al (1995) Response of L-929 fibroblasts, human gingival fibroblasts, and human tissue mast cells to various metal cations. J Dent Res 74(8):1513–1520

    Article  CAS  PubMed  Google Scholar 

  24. Gousias K, Theocharous T, Simon M (2022) Mech Cell Cycle Arrest Apoptosis Glioblastoma Biomedicines 10(3):564

    CAS  Google Scholar 

  25. Zhang Y et al (2021) Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR. Phytother Res 35(11):6377–6388

    Article  CAS  PubMed  Google Scholar 

  26. Hernández Borrero LJ, El-Deiry WS (2021) Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1876(1):188556

  27. Das B, Sahoo S, Mallick B (2022) HIWI2 induces G2/M cell cycle arrest and apoptosis in human fibrosarcoma via the ROS/DNA damage/p53 axis. Life Sci 293:120353

    Article  CAS  PubMed  Google Scholar 

  28. Engeland K (2022) Cell cycle regulation: p53-p21-RB signaling. Cell Death & Differentiation 29(5):946–960

    Article  CAS  Google Scholar 

  29. Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities Nat Rev Cancer, 9(6):400–14

  30. Redza-Dutordoir M, Averill-Bates DA (2016) Activation of apoptosis signalling pathways by reactive oxygen species Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1863:2977–299212

  31. Siddiqui H et al (2017) Harmaline and its derivatives against the infectious Multi-Drug Resistant Escherichia coli. Med Chem 13(5):465–476

    Article  CAS  PubMed  Google Scholar 

  32. Li S-P et al (2018) Analogous β-Carboline alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by attenuating acetylcholinesterase activity, oxidative stress, and inflammation in mice. Frontiers in Pharmacology, p 9

  33. Paromita B et al (2018) Therapeutic potential of harmaline, a novel alkaloid, against cervical cancer cells in vitro: apoptotic induction and DNA interaction study. J Appl Biology Biotechnol 6(4):1–8

    Google Scholar 

  34. Ebrahimi S, Soltani A, Hashemy SI (2019) Oxidative stress in cervical cancer pathogenesis and resistance to therapy. J Cell Biochem 120(5):6868–6877

    Article  CAS  PubMed  Google Scholar 

  35. He Z, Simon HU (2013) A novel link between p53 and ROS. Cell Cycle 12(2):201–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jalili-Nik M et al (2019) Cytotoxic Effects of Ferula Latisecta on Human Glioma U87 cells. Drug Res (Stuttg) 69(12):665–670

    Article  CAS  PubMed  Google Scholar 

  37. Kumar R et al (2018) Demethoxycurcumin mediated targeting of MnSOD leading to activation of apoptotic pathway and inhibition of Akt/NF-κB survival signalling in human glioma U87 MG cells. Toxicol Appl Pharmacol 345:75–93

    Article  CAS  PubMed  Google Scholar 

  38. Hamsa TP, Kuttan G (2010) Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. Eur J Pharmacol 649(1–3):64–73

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study supported by Mashhad University of Medical Sciences (code: 4010356).

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

      Mohammad Mahdi Vahedi

    2. Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

      Ali Shahini, Mehran Mottahedi & Setareh Garousi

    3. Neurosurgery Department, Ghaem Hospital, Mashhad university of medical sciences, Mashhad, Iran

      Seyed Ali Shariat Razavi

    4. Department of medical laboratory science, Mashhad branch, Islamic Azad University, Mashhad, Iran

      Ghazaleh pouyamanesh

    5. Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

      Amir R. Afshari

    6. Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, BN1 9PH, UK

      Gordon A. Ferns

    7. Clinical Research Development Unit, Faculty of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

      Afsane Bahrami

    8. Clinical Research Development Unit of Akbar Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

      Afsane Bahrami

    Authors
    1. Mohammad Mahdi Vahedi
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ali Shahini
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Mehran Mottahedi
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Setareh Garousi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Seyed Ali Shariat Razavi
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ghazaleh pouyamanesh
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Amir R. Afshari
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Gordon A. Ferns
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Afsane Bahrami
      View author publications

      You can also search for this author in PubMed Google Scholar

    Contributions

    AB: Methodology, Conceptualization, Formal analysis, Validation, Funding acquisition, Writing - original draft. MMV: Formal analysis, Validation, Writing - review & editing. AS: Methodology, Formal analysis, Validation. MM: Resources, Supervision, Writing - review & editing. SG: Methodology, Formal analysis, Validation. SASR: Validation, Writing - review & editing. GP: Resources, Supervision, Writing - review & editing. AA Methodology, Formal analysis, Validation. GF: Supervision, review & editing. All Authors read and confirmed the manuscript.

    Corresponding author

    Correspondence to Afsane Bahrami.

    Ethics declarations

    Competing interests

    The authors declare that there is no conflict of interest.

    Ethical approval

    The study was approved by the Deputy of Research and Technology and Ethics Committee of Mashhad University of Medical Sciences (IR.MUMS.MEDICAL.REC.1401.322).

    Consent to participate

    Not applicable.

    Consent to publish

    Not applicable.

    Additional information

    Publisher’s Note

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

    Ali Shahini and Mohammad Mahdi Vahedi are equal contributors as first author.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary Material 1

    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

    Vahedi, M., Shahini, A., Mottahedi, M. et al. Harmaline exerts potentially anti-cancer effects on U-87 human malignant glioblastoma cells in vitro. Mol Biol Rep 50, 4357–4366 (2023). https://doi.org/10.1007/s11033-023-08354-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11033-023-08354-z

    Keywords

    Search

    Navigation