Skip to main content

Advertisement

SpringerLink
Log in

Anti-tumor effect of berberine on chronic lymphocytic leukemia cells

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

Abstract

Chronic lymphocytic leukemia (CLL) is a blood malignancy that is characterized by remarkable expression of CD69 and Ki67 in CLL cells. Elevated levels of Cleaved-Poly (ADP-ribose) polymerase-1 (PARP1) and microRNA-155 (MiR-155) are related to poor prognosis of disease. Berberine as a natural isoquinoline alkaloid, has shown an anti-tumor potential in tumor cells. The objective of present study was to explore some aspects of molecular mechanisms of berberine effect in CLL cells. To analyze the expression of CD69 and Ki67 using flow cytometry, 16 peripheral blood samples and seven bone marrow aspirates were collected from CLL patients. Isolated peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) were treated with 25 µM of berberine for 24 h. The level of miR-155 expression was subsequently evaluated by real-time PCR. Furthermore, western blot was used for assessment of cleaved PARP1. Our results demonstrated a significant reduction in CD69 and Ki67 expression on CD19+ cells when the cells were treated by berberine. Interestingly, the expression level of miR-155 was reduced after berberine treatment in compare to the control group. Furthermore, western blotting revealed an increased level of cleaved PARP1 in dose-dependently manner in CLL cells. The results confirmed the anti-tumor impact of berberine on CLL cells through reducing CD69, Ki67, and miR-155 expression and increasing cleaved PARP1 may be considered as an option for future clinical studies.

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

All data that support the findings of this study are included in this published article. Further details are available upon request.

References

  1. Burger JA, O’Brien S. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510–27.

    Article  CAS  PubMed  Google Scholar 

  2. Sun X, et al. Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells. Mol Cell Biol. 2017;37(17):e00569-e616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. AL-Mudallal SS, Jasim HN. Evaluation of Bcl 2 and Ki 67 expression in Chronic Lymphocytic Leukemia. J Faculty Med Baghdad. 2012;54(4):335–9.

    Google Scholar 

  4. Tan M-F, et al. Expression of ki-67 in chronic lymphocytic leukemia and its clinical significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015;23(2):318–21.

    CAS  PubMed  Google Scholar 

  5. Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Balatti V, et al. Novel mechanisms of regulation of miRNAs in CLL. Trends in cancer. 2016;2(3):134–43.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Aref S, et al. Prognostic relevance of CD69 expression in B cell chronic lymphocytic leukemia. Comp Clin Pathol. 2019;28(1):33–40.

    Article  CAS  Google Scholar 

  8. Diamantopoulos PT, et al. PARP1-driven apoptosis in chronic lymphocytic leukemia. BioMed Res Int. 2014. https://doi.org/10.1155/2014/106713.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ayati SH, et al. Regulatory effects of berberine on microRNome in cancer and other conditions. Crit Rev Oncol Hematol. 2017;116:147–58.

    Article  PubMed  Google Scholar 

  10. Wang Y, et al. The anti-cancer mechanisms of berberine: a review. Cancer Manag Res. 2020;12:695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mohammadlou M, et al. Apoptotic effect of berberine via Bcl-2, ROR1, and mir-21 in patients with B-chronic lymphocytic leukemia. Phytother Res. 2021;35(4):2025–33.

    Article  CAS  PubMed  Google Scholar 

  12. Hallek M, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–60.

    Article  CAS  PubMed  Google Scholar 

  13. Ghahremanfard F, et al. Effect of berberine on cancer cell viability of chronic lymphocytic leukemia patients in in vitro. Koomesh. 2017;19(3):634–40.

    Google Scholar 

  14. Schwarzenbach H, et al. Data normalization strategies for microRNA quantification. Clin Chem. 2015;61(11):1333–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jain P, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maude SL, et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ciszak L, et al. Patients with chronic lymphocytic leukaemia (CLL) differ in the pattern of CTLA-4 expression on CLL cells: the possible implications for immunotherapy with CTLA-4 blocking antibody. Tumor Biology. 2016;37(3):4143–57.

    Article  CAS  PubMed  Google Scholar 

  18. Endl E, Gerdes J. The Ki-67 protein: fascinating forms and an unknown function. Exp Cell Res. 2000;257(2):231–7.

    Article  CAS  PubMed  Google Scholar 

  19. Khoudoleeva O, et al. Proliferative index and expression of CD38, Zap-70, and CD25 in different lymphoid compartments of chronic lymphocytic leukemia patients. Pathol Lab Med. 2011;3:7–16.

    Google Scholar 

  20. Wang L, et al. Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells. PLoS ONE. 2013;8(2): e56666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Murthy KNC, Jayaprakasha GK, Patil BS. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur J Pharmacol. 2012;688(1–3):14–21.

    Article  Google Scholar 

  22. Yan K, et al. Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells. Eur J Pharmacol. 2011;661(1–3):1–7.

    Article  CAS  PubMed  Google Scholar 

  23. Tak J, et al. Berberine enhances posttranslational protein stability of p21/cip1 in breast cancer cells via down-regulation of Akt. Mol Cell Biochem. 2019;458(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  24. Cui B, et al. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood. 2014;124(4):546–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pandey MK, et al. Berberine modifies cysteine 179 of IκBα kinase, suppresses nuclear factor-κB–regulated antiapoptotic gene products, and potentiates apoptosis. Can Res. 2008;68(13):5370–9.

    Article  CAS  Google Scholar 

  26. Hou D, et al. Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition. Cell Death Dis. 2017;8(10):e3070–e3070.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Patil JB, Kim J, Jayaprakasha G. Berberine induces apoptosis in breast cancer cells (MCF-7) through mitochondrial-dependent pathway. Eur J Pharmacol. 2010;645(1–3):70–8.

    Article  CAS  PubMed  Google Scholar 

  28. Del Poeta G, et al. CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study. Haematologica. 2012;97(2):279.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Xu L, Liu Y, He X. Inhibitory effects of berberine on the activation and cell cycle progression of human peripheral lymphocytes. Cell Mol Immunol. 2005;2(4):295–300.

    CAS  PubMed  Google Scholar 

  30. Herman SE, et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen Y-X, et al. Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study. Lancet Gastroenterol Hepatol. 2020;5(3):267–75.

    Article  PubMed  Google Scholar 

  32. Zhang J, et al. Berberine potently attenuates intestinal polyps growth in ApcMin mice and familial adenomatous polyposis patients through inhibition of Wnt signalling. J Cell Mol Med. 2013;17(11):1484–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu J, et al. Anticancer effect of berberine based on experimental animal models of various cancers: a systematic review and meta-analysis. BMC Cancer. 2019;19(1):1–20.

    Article  Google Scholar 

  34. Chu S-C, et al. Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells. Mol Pharmacol. 2014;86(6):609–23.

    Article  PubMed  Google Scholar 

  35. Zhang P, et al. Berberine inhibits growth of liver cancer cells by suppressing glutamine uptake. Onco Targets Ther. 2019;12:11751–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to express our sincere gratitude to the Clinical Research Development Unit of Kosar Hospital and Semnan University of Medical Sciences for cooperation in this work.

Funding

This work was supported by a grant from Semnan University of Medical Sciences (Grant No.1490).

Author information

Author notes

  1. Farahnaz Ghahremanfard and Parviz Kokhaei have contributed equally to the study.

Authors and Affiliations

  1. Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Maryam Abdollahi, Maryam Mohammadlou, Maral Hemati, Rasoul Baharlou, Farahnaz Ghahremanfard & Mohammad Amir Sarabi

  2. Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran

    Maryam Abdollahi & Maryam Mohammadlou

  3. Department of Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran

    Parviz Kokhaei

  4. Department of Immunology, Genetics & Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Ehsan Manouchehri Doulabi

  5. Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden

    Parviz Kokhaei

Authors
  1. Maryam Abdollahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam Mohammadlou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maral Hemati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rasoul Baharlou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ehsan Manouchehri Doulabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Farahnaz Ghahremanfard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohammad Amir Sarabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Parviz Kokhaei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PK and FG conceived and planned the experiments. MA, MM, MH, and EMD carried out the experiments. MA wrote the manuscript. MA, MM, and MAS contributed to sample preparation. RB analyzed the results. RB and PK contributed to the interpretation of the results. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Corresponding authors

Correspondence to Farahnaz Ghahremanfard or Parviz Kokhaei.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

The study complied with the guidelines for human studies and was conducted in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the Ethical Board of the Semnan University of Medical Sciences (IR.SEMUMS.REC.1379.181).

Consent to participate

Written informed consent was obtained from all individuals.

Consent for publication

Not applicable, as data of the study was anonymous.

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 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

Abdollahi, M., Mohammadlou, M., Hemati, M. et al. Anti-tumor effect of berberine on chronic lymphocytic leukemia cells. Med Oncol 39, 217 (2022). https://doi.org/10.1007/s12032-022-01818-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-022-01818-5

Keywords

Search

Navigation