Skip to main content
SpringerLink
Log in

Combretastatin A-4 suppresses the invasive and metastatic behavior of glioma cells and induces apoptosis in them: in-vitro study

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

Abstract

The most common primary brain malignancy, glioblastoma multiforme, is tremendously resistant to conventional treatments due to its potency for metastasis to surrounding brain tissue. Temozolomide is a chemotherapeutic agent that currently is administrated during the treatment procedure. Studies have attempted to investigate new agents with higher effectiveness and fewer side effects. Combretastatin A-4 (CA-4), a natural compound derived from Combretum caffrum, has been recently considered for its potent antitumor activities in a wide variety of preclinical solid tumor models. Our findings have shown that CA-4 exerts potent anti-proliferative and apoptotic effects on glioma cells, and ROS generation may be involved in these cellular events. CA-4 has imposed G2 arrest in U-87 cells. We also observed that CA-4 significantly reduced the migration and invasion capability of U-87 cells. Furthermore, the gene expression and enzyme activity of MMP-2 and MMP-9 were significantly inhibited in the presence of CA-4. We also observed a considerable decrease in PI3K and Akt protein expression following treatment with CA-4. In conclusion, our findings showed significant apoptogenic and anti-metastatic effects of CA-4 on glioma cells and also suggested that the PI3K/Akt/MMP-2/-9 and also ROS pathway might play roles in these cellular events.

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

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article. More details and raw data will be available upon request.

References

  1. Dimov I, et al. Glioblastoma multiforme stem cells. ScientificWorldJournal. 2011;11:930–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Maghrouni A, et al. Targeting the PD-1/PD-L1 pathway in glioblastoma multiforme: Preclinical evidence and clinical interventions. Int Immunopharmacol. 2021;93: 107403.

    Article  CAS  PubMed  Google Scholar 

  3. Afshari AR, et al. Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS). EXCLI J. 2019;18:576–90.

    PubMed  PubMed Central  Google Scholar 

  4. Afshari AR, et al. Effects of statins on brain tumors: a review. Semin Cancer Biol. 2020;73:116.

    Article  PubMed  Google Scholar 

  5. Afshari AR, Mollazadeh H, Sahebkar A. Minocycline in treating glioblastoma multiforme: far beyond a conventional antibiotic. J Oncol. 2020;2020:8659802.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Soukhtanloo M, et al. Natural products as promising targets in glioblastoma multiforme: a focus on NF-κB signaling pathway. Pharmacol Rep. 2020;72(2):285–95.

    Article  PubMed  Google Scholar 

  7. Afshari AR, et al. Protective role of natural products in glioblastoma multiforme: a focus on nitric oxide pathway. Curr Med Chem. 2021;28(2):377–400.

    Article  CAS  PubMed  Google Scholar 

  8. Ng QS, et al. Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;67(5):1375–80.

    Article  CAS  PubMed  Google Scholar 

  9. Pettit GR, et al. Antineoplastic agents 322. synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des. 1995;10(4):299–309.

    CAS  PubMed  Google Scholar 

  10. Zhao D, et al. Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI. Faseb j. 2008;22(7):2445–51.

    Article  CAS  PubMed  Google Scholar 

  11. Nik ME, et al. Targeted-nanoliposomal combretastatin A4 (CA-4) as an efficient antivascular candidate in the metastatic cancer treatment. J Cell Physiol. 2019;234:14721.

    Article  CAS  PubMed  Google Scholar 

  12. Qin H, et al. PI3Kgamma inhibitor attenuates immunosuppressive effect of Poly(l-Glutamic Acid)-combretastatin A4 conjugate in metastatic breast cancer. Adv Sci (Weinh). 2019;6(12):1900327.

    Article  PubMed  Google Scholar 

  13. Zhang C, et al. Anti-cancer effect of metabotropic glutamate receptor 1 inhibition in human glioma U87 cells: involvement of PI3K/Akt/mTOR pathway. Cell Physiol Biochem. 2015;35(2):419–32.

    Article  CAS  PubMed  Google Scholar 

  14. Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol. 1999;43(Suppl):S42-51.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang S, et al. Autophagy- and MMP-2/9-mediated reduction and redistribution of ZO-1 contribute to hyperglycemia-increased blood-brain barrier permeability during early reperfusion in stroke. Neuroscience. 2018;377:126–37.

    Article  CAS  PubMed  Google Scholar 

  16. Liu Y, et al. Fucoxanthin activates apoptosis via inhibition of PI3K/Akt/mTOR pathway and suppresses invasion and migration by restriction of p38-MMP-2/9 pathway in human glioblastoma cells. Neurochem Res. 2016;41(10):2728–51.

    Article  CAS  PubMed  Google Scholar 

  17. Chen G, et al. Plumbagin suppresses the migration and invasion of glioma cells via downregulation of MMP-2/9 expression and inaction of PI3K/Akt signaling pathway in vitro. J Pharmacol Sci. 2017;134(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  18. Rodriguez LG, Wu X, Guan JL. Wound-healing assay. Methods Mol Biol. 2005;294:23–9.

    PubMed  Google Scholar 

  19. Vandooren J, et al. Zymography methods for visualizing hydrolytic enzymes. Nat Methods. 2013;10(3):211–20.

    Article  CAS  PubMed  Google Scholar 

  20. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  21. Mohtashami E, et al. The current state of potential therapeutic modalities for glioblastoma multiforme: a clinical review. Curr Drug Metab. 2020;21(8):564–78.

    Article  CAS  PubMed  Google Scholar 

  22. Sherbet GV. Combretastatin analogues in cancer biology: A prospective view. J Cell Biochem. 2020;121(3):2127–38.

    Article  CAS  PubMed  Google Scholar 

  23. Nathan P, et al. Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer. Clin Cancer Res. 2012;18(12):3428–39.

    Article  CAS  PubMed  Google Scholar 

  24. Kamal A, et al. Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents. Bioorg Med Chem Lett. 2016;26(12):2957–64.

    Article  CAS  PubMed  Google Scholar 

  25. Yan J, et al. A novel synthetic compound exerts effective anti-tumour activity in vivo via the inhibition of tubulin polymerisation in A549 cells. Biochem Pharmacol. 2015;97(1):51–61.

    Article  CAS  PubMed  Google Scholar 

  26. Tian J, et al. Scoulerine promotes cell viability reduction and apoptosis by activating ROS-dependent endoplasmic reticulum stress in colorectal cancer cells. Chem Biol Interact. 2020;327: 109184.

    Article  CAS  PubMed  Google Scholar 

  27. Kanthou C, et al. The tubulin-binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death. Am J Pathol. 2004;165(4):1401–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Patterson JC, et al. ROS and oxidative stress are elevated in mitosis during asynchronous cell cycle progression and are exacerbated by mitotic arrest. Cell Syst. 2019;8(2):163-167.e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karimi Roshan M, et al. Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process. Biochimie. 2019;165:229–34.

    Article  CAS  PubMed  Google Scholar 

  30. Jalili-Nik M, et al. Cytotoxic effects of ferula latisecta on human glioma U87 cells. Drug Res (Stuttg). 2019;69(12):665–70.

    Article  CAS  PubMed  Google Scholar 

  31. Choe G, et al. Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype. Clin Cancer Res. 2002;8(9):2894–901.

    CAS  PubMed  Google Scholar 

  32. Wang C, et al. Effect of matrix metalloproteinase-mediated matrix degradation on glioblastoma cell behavior in 3D PEG-based hydrogels. J Biomed Mater Res A. 2017;105(3):770–8.

    Article  CAS  PubMed  Google Scholar 

  33. Sun LC, et al. A conjugate of camptothecin and a somatostatin analog against prostate cancer cell invasion via a possible signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9. Cancer Lett. 2007;246(1–2):157–66.

    Article  CAS  PubMed  Google Scholar 

  34. Mirzavi F, et al. Pegylated liposomal encapsulation improves the antitumor efficacy of combretastatin A4 in murine 4T1 triple-negative breast cancer model. Int J Pharm. 2022;613: 121396.

    Article  CAS  PubMed  Google Scholar 

  35. Gloushankova NA, Rubtsova SN, Zhitnyak IY. Cadherin-mediated cell-cell interactions in normal and cancer cells. Tissue Barriers. 2017;5(3): e1356900.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lu Y, et al. Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate. 2006;66(12):1311–8.

    Article  CAS  PubMed  Google Scholar 

  37. Dagouassat M, et al. Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. Int J Cancer. 2010;126(5):1095–108.

    Article  CAS  PubMed  Google Scholar 

  38. Dwyer RM, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res. 2007;13(17):5020–7.

    Article  CAS  PubMed  Google Scholar 

  39. Dwyer J, et al. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2. PLoS ONE. 2012;7(9): e45562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen JS, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol Res. 2009;39(2):177–86.

    Article  CAS  PubMed  Google Scholar 

  41. Li X, et al. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 2016;7(22):33440–50.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wang H, et al. Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest. 2004;84(8):941–51.

    Article  CAS  PubMed  Google Scholar 

  43. Sonoda Y, et al. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res. 2001;61(18):6674–8.

    CAS  PubMed  Google Scholar 

  44. Kapitonov D, et al. Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res. 2009;69(17):6915–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jo H, Loison F, Luo HR. Microtubule dynamics regulates Akt signaling via dynactin p150. Cell Signal. 2014;26(8):1707–16.

    Article  CAS  PubMed  Google Scholar 

  46. Liang W, et al. Combretastatin A4 regulates proliferation, migration, invasion, and apoptosis of thyroid cancer cells via PI3K/Akt signaling pathway. Med Sci Monit. 2016;22:4911–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Barber AG, et al. PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer. Cancer Med. 2015;4(8):1258–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Mashhad University of Medical Sciences, Mashhad, Iran. Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran. Funding number: 970217.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mostafa Karimi Roshan & Mohammad Soukhtanloo

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

    Amir R. Afshari

  3. Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran

    Farshad Mirzavi

  4. Pharmacological Research Center of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Hadi Mousavi & Mohammad Soukhtanloo

Authors
  1. Mostafa Karimi Roshan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amir R. Afshari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Farshad Mirzavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seyed Hadi Mousavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Soukhtanloo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MKR, ARA, SHM, MS—Study conception and design. AMR, FM, MKR—Acquisition of data. MKR, SHM—Analysis and interpretation of data. MKR, ARA—Drafting of the manuscript. SHM, MS, ARA—Critical revision.

Corresponding author

Correspondence to Mohammad Soukhtanloo.

Ethics declarations

Conflict of interest

None.

Consent to participate

This was a cell base study, with no human sample included.

Consent for publication

The authors declare there is not any conflict of interest related to the publication of this article.

Additional information

Publisher's Note

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

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

Roshan, M.K., Afshari, A.R., Mirzavi, F. et al. Combretastatin A-4 suppresses the invasive and metastatic behavior of glioma cells and induces apoptosis in them: in-vitro study. Med Oncol 40, 331 (2023). https://doi.org/10.1007/s12032-023-02197-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-023-02197-1

Keywords

Search

Navigation