Skip to main content

Advertisement

SpringerLink
Log in

Molecular effects of genistein, as a potential anticancer agent, on CXCR-4 and VEGF pathway in acute lymphoblastic leukemia

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

Abstract

Background

Vascular endothelial growth factor (VEGF) is one of the angiogenic mediators that can be secreted by leukemic cells and plays an important role in tumor invasion and metastasis. Another important agent contributing to the relapse of ALL is C-X-C chemokine receptor type-4 (CXCR-4), expression of this receptor in cancer cells has been related to metastasis. It has been identified that genistein—a soy-derived isoflavonoid—has anti-angiogenesis functions. We aimed to show the effects of this compound on VEGF and CXCR-4 in Acute lymphoblastic leukemia (ALL) cell models.

Methods and results

The cytotoxicity of Genistein was measured using the MTS colorimetric assay. After being treated with Genistein, the expression of VEGF in mRNA and protein levels was measured in MOLT-4 and Jurkat cells. We also used flow cytometry assay to determine the expression of CXCR-4 in cell surfaces. We found that Genistein decreased cell viability in two cell models while was more effective on MOLT-4 cells. After Genistein-treatment, surface expression levels of CXCR-4 were decreased, while VEGF secretion and mRNA expression levels were increased in MOLT-4 and Jurkat cells.

Conclusions

The results suggest that Genistein may not be a reliable choice for the treatment of ALL; however, this different identified pattern can be useful for the recognition of VEGF and CXCR-4 modulators and thus for planning new treatments for leukemia and other VEGF related disorders.

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

Similar content being viewed by others

References

  1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P et al (1995) A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811.

  2. Münch V, Trentin L, Herzig J, Demir S, Seyfried F, Kraus JM et al (2017) Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor. Blood 130(5):643–654

    Article  PubMed  Google Scholar 

  3. Koomagi R, Zintl F, Sauerbrey A, Volm M (2001) Vascular endothelial growth factor in newly diagnosed and recurrent childhood acute lymphoblastic leukemia as measured by real-time quantitative polymerase chain reaction. Clin Cancer Res 7(11):3381–3384

    CAS  PubMed  Google Scholar 

  4. Rashidi B, Malekzadeh M, Goodarzi M, Masoudifar A, Mirzaei H (2017) Green tea and its anti-angiogenesis effects. Biomed Pharmacother 89:949–956

    Article  CAS  PubMed  Google Scholar 

  5. Duffy AM, Bouchier-Hayes DJ, Harmey JH (2013) Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signalling by VEGF. Landes Bioscience, Madame Curie Bioscience Database [Internet]

    Google Scholar 

  6. Markovic A, MacKenzie KL, Lock RB (2012) Induction of vascular endothelial growth factor secretion by childhood acute lymphoblastic leukemia cells via the FLT-3 signaling pathway. Mol Cancer Ther 11(1):183–193

    Article  CAS  PubMed  Google Scholar 

  7. Wang L, Zhang W, Ding Y, Xiu B, Li P, Dong Y et al (2015) Up-regulation of VEGF and its receptor in refractory leukemia cells. Int J Clin Exp Pathol 8(5):5282

    PubMed  PubMed Central  Google Scholar 

  8. Leblebisatan G, Antmen B, Şaşmaz İ, Kilinç Y (2012) Vascular endothelial growth factor levels in childhood acute lymphoblastic and myeloblastic leukemia. Indian J Hematol Blood Transfusion 28(1):24–28

    Article  Google Scholar 

  9. Demacq C, Vasconcellos VB, Izidoro-Toledo TC, da Silva Silveira V, Canalle R, de Paula Queiroz RG et al (2010) Vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (NOS3) polymorphisms are associated with high relapse risk in childhood acute lymphoblastic leukemia (ALL). Clin Chim Acta 411(17–18):1335–1340

    Article  CAS  PubMed  Google Scholar 

  10. Tavor S, Petit I (eds) (2010) Can inhibition of the SDF-1/CXCR4 axis eradicate acute leukemia? Seminars in cancer biology, Elsevier, UK

  11. Burger JA, Bürkle A (2007) The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target. Br J Haematol 137(4):288–296

    Article  CAS  PubMed  Google Scholar 

  12. Mowafi F, Cagigi A, Matskova L, Björk O, Chiodi F, Nilsson A (2008) Chemokine CXCL12 enhances proliferation in pre-B‐ALL via STAT5 activation. Pediatr Blood Cancer 50(4):812–817

    Article  PubMed  Google Scholar 

  13. Mirshahi P, Rafii A, Vincent L, Berthaut A, Varin R, Kalantar G et al (2009) Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia 23(6):1039–1048

    Article  CAS  PubMed  Google Scholar 

  14. Zlotnik A (2006) Involvement of chemokine receptors in organ-specific metastasis. Infection and inflammation: impacts on oncogenesis, vol 13. Karger Publishers, pp 191–199

  15. Pitt LA, Tikhonova AN, Trimarchi T, King B, Hu H, Gong Y et al (2015) Abstract A06: The chemokine receptor CXCR4 is essential for the maintenance of T cell acute lymphoblastic leukemia. AACR

  16. Masiero M, Minuzzo S, Pusceddu I, Moserle L, Persano L, Agnusdei V et al (2011) Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. Leukemia 25(4):588–598

    Article  CAS  PubMed  Google Scholar 

  17. Brzozowa M, Mielańczyk Ł, Michalski M, Malinowski Ł, Kowalczyk-Ziomek G, Helewski K et al (2013) Role of Notch signaling pathway in gastric cancer pathogenesis. Contem Oncol 17(1):1

    CAS  Google Scholar 

  18. Ferrandino F, Bernardini G, Tsaouli G, Grazioli P, Campese AF, Noce C et al (2018) Intrathymic Notch3 and CXCR4 combinatorial interplay facilitates T-cell leukemia propagation. Oncogene 37(49):6285–6298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Simon T, Gagliano T, Giamas G (2017) Direct effects of anti-angiogenic therapies on tumor cells: VEGF signaling. Trends Mol Med 23(3):282–292

    Article  CAS  PubMed  Google Scholar 

  20. Mukherjee D, Zhao J (2013) The Role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res 3(1):46

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Teicher BA (2011) Antiangiogenic agents and targets: A perspective. Biochem Pharmacol 81(1):6–12

    Article  CAS  PubMed  Google Scholar 

  22. Franco R, Botti G, Mascolo M, Loquercio G, Liguori G, Ilardi G et al (2010) CXCR4-CXCL12 and VEGF correlate to uveal melanoma progression. Front Biosci (Elite Ed) 2:13–21

    Article  Google Scholar 

  23. Uemae Y, Ishikawa E, Osuka S, Matsuda M, Sakamoto N, Takano S et al (2014) CXCL12 secreted from glioma stem cells regulates their proliferation. J Neurooncol 117(1):43–51

    Article  CAS  PubMed  Google Scholar 

  24. Raynal NJ-M, Momparler L, Charbonneau M, Momparler RL (2008) Antileukemic activity of genistein, a major isoflavone present in soy products. J Nat Prod 71(1):3–7

    Article  CAS  PubMed  Google Scholar 

  25. Mazumder MAR, Hongsprabhas P (2016) Genistein as antioxidant and antibrowning agents in in vivo and in vitro: A review. Biomed Pharmacother 82:379–392

    Article  Google Scholar 

  26. Russo M, Russo GL, Daglia M, Kasi PD, Ravi S, Nabavi SF et al (2016) Understanding genistein in cancer: The “good” and the “bad” effects: A review. Food Chem 196:589–600

    Article  CAS  PubMed  Google Scholar 

  27. Giles FJ (2001) The vascular endothelial growth factor (VEGF) signaling pathway: a therapeutic target in patients with hematologic malignancies. Oncologist 6:32–39

    Article  CAS  PubMed  Google Scholar 

  28. Ghaffari-Makhmalbaf P, Sayyad M, Pakravan K, Razmara E, Bitaraf A, Bakhshinejad B et al (2020) Docosahexaenoic acid reverses the promoting effects of breast tumor cell-derived exosomes on endothelial cell migration and angiogenesis. Life Sci 264

  29. Poursheikhani A, Bahmanpour Z, Razmara E, Mashouri L, Taheri M, Yousefi H et al (2020) Non-coding RNAs underlying chemoresistance in gastric cancer. Cellular Oncol. 43:961–988

    Article  CAS  Google Scholar 

  30. Hai-Xin L, Yu W, Qing L, Ming-Zhu Y, Guan-Wei F, Karas RH et al (2016) Bidirectional regulation of angiogenesis by phytoestrogens through estrogen receptor-mediated signaling networks. Chin J Nat Med 14(4):241–254

    Google Scholar 

  31. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 – ∆∆CT method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  32. Sak K, Everaus H (2015) Multi-target cytotoxic actions of flavonoids in blood cancer cells. Asian Pac J Cancer Prev 16:4843–4847

    Article  PubMed  Google Scholar 

  33. Renault TT, Chipuk JE (2014) Death upon a kiss: mitochondrial outer membrane composition and organelle communication govern sensitivity to BAK/BAX-dependent apoptosis. Chem Biol 21(1):114–123

    Article  CAS  PubMed  Google Scholar 

  34. Razmara E, Bitaraf A, Yousefi H, Nguyen TH, Garshasbi M, Cho WC-s et al (2019) Non-coding RNAs in cartilage development: An updated review. Int J Mol Sci 20(18):4475

    Article  CAS  PubMed Central  Google Scholar 

  35. Barnabas O, Wang H, Gao X-M (2013) Role of estrogen in angiogenesis in cardiovascular diseases. Journal of geriatric cardiology: JGC 10(4):377

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Huh J-E, Nam D-W, Baek Y-H, Kang JW, Park D-S, Choi D-Y et al (2011) Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways. Int Immunopharmacol 11(1):46–54

    Article  CAS  PubMed  Google Scholar 

  37. Yoo PS, Mulkeen AL, Cha CH (2006) Post-transcriptional regulation of vascular endothelial growth factor: implications for tumor angiogenesis. World journal of gastroenterology: WJG 12(31):4937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Arcondéguy T, Lacazette E, Millevoi S, Prats H, Touriol C (2013) VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res 41(17):7997–8010

    Article  PubMed  PubMed Central  Google Scholar 

  39. Liu D, Homan LL, Dillon JS (2004) Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5′-monophosphate-dependent mechanism. Endocrinology 145(12):5532–5539

    Article  CAS  PubMed  Google Scholar 

  40. Yen L, You X-L, Al Moustafa A-E, Batist G, Hynes NE, Mader S et al (2000) Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19(31):3460–3469

    Article  CAS  PubMed  Google Scholar 

  41. Levy AP, Levy NS, Goldberg MA (1996) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271(5):2746–2753

    Article  CAS  PubMed  Google Scholar 

  42. Dulak J, Józkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D et al (2000) Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20(3):659–666

    Article  CAS  PubMed  Google Scholar 

  43. Papapetropoulos A, García-Cardeña G, Madri JA, Sessa WC (1997) Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Investig 100(12):3131–3139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bouloumié A, Schini-Kerth VB, Busse R (1999) Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells. Cardiovascular Res 41(3):773–780

    Article  Google Scholar 

  45. Abe H, Ishikawa W, Kushima T, Nishimura T, Mori C, Onuki A et al (2013) Nitric oxide induces vascular endothelial growth factor expression in the rat placenta in vivo and in vitro. Biosci Biotechnol Biochem 77(5):971–976

    Article  CAS  PubMed  Google Scholar 

  46. Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D’Acquisto F et al (2000) Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood J Am Soc Hematol 95(1):189–197

    CAS  Google Scholar 

  47. Kasuno K, Takabuchi S, Fukuda K, Kizaka-Kondoh S, Yodoi J, Adachi T et al (2004) Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling. J Biol Chem 279(4):2550–2558

    Article  CAS  PubMed  Google Scholar 

  48. Nagy G, Koncz A, Fernandez D, Perl A (2007) Nitric oxide, mitochondrial hyperpolarization, and T cell activation. Free Radic Biol Med 42(11):1625–1631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gasteiger E, Hoogland C, Gattiker A, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy server. Methods Mol Biol 112:571–607

    Google Scholar 

  50. Hsu EL, Chen N, Westbrook A, Wang F, Zhang R, Taylor RT et al (2009) Modulation of CXCR4, CXCL12, and tumor cell invasion potential in vitro by phytochemicals. J Oncol 2009

  51. Uifălean A, Schneider S, Ionescu C, Lalk M, Iuga CA (2016) Soy isoflavones and breast cancer cell lines: molecular mechanisms and future perspectives. Molecules 21(1):13

    Article  Google Scholar 

  52. Al-Souhibani N, Al-Ghamdi M, Al-Ahmadi W, Khabar KS (2014) Posttranscriptional control of the chemokine receptor CXCR4 expression in cancer cells. Carcinogenesis 35(9):1983–1992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Grumbach IM, Chen W, Mertens SA, Harrison DG (2005) A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothelial nitric oxide synthase transcription. J Mol Cell Cardiol 39(4):595–603

    Article  CAS  PubMed  Google Scholar 

  54. Kiani AA, Elyasi H, Ghoreyshi S, Nouri N, Safarzadeh A, Nafari A (2021) Study on hypoxia-inducible factor and its roles in immune system.Immunological Medicine. :1–14

  55. D’Ignazio L, Bandarra D, Rocha S (2016) NF-κB and HIF crosstalk in immune responses. FEBS J 283(3):413–424

    Article  PubMed  Google Scholar 

  56. D’Ignazio L, Batie M, Rocha S (2017) Hypoxia and inflammation in cancer, focus on HIF and NF-κB. Biomedicines 5(2):21

    Article  PubMed Central  Google Scholar 

  57. Nam S, Ko Y, Jung J, Yoon J, Kim Y, Choi Y et al (2011) A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κ B promotes gastric tumour growth and angiogenesis. Br J Cancer 104(1):166–174

    Article  CAS  PubMed  Google Scholar 

  58. Javed Z, Khan K, Herrera-Bravo J, Naeem S, Iqbal MJ, Sadia H et al (2021) Genistein as a regulator of signaling pathways and microRNAs in different types of cancers. Cancer Cell Int 21(1):1–12

    Article  Google Scholar 

  59. Tuli HS, Tuorkey MJ, Thakral F, Sak K, Kumar M, Sharma AK et al (2019) Molecular mechanisms of action of genistein in cancer: Recent advances. Front Pharmacol 10:1336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cui H-B, Na X-L, Song D-F, Liu Y (2005) Blocking effects of genistein on cell proliferation and possible mechanism in human gastric carcinoma. World J Gastroenterol 11(1):69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Traganos F, Ardelt B, Halko N, Bruno S, Darzynkiewicz Z (1992) Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res 52(22):6200–6208

    CAS  PubMed  Google Scholar 

  62. Zhao W, Qin Y, Niu Z, Chang C, Yang J, Li M et al (2016) Branches of the NF-kappaB signaling pathway regulate proliferation of oval cells in rat liver regeneration. Genet Mol Res 15:gmr7750

    Google Scholar 

  63. Bianchi ME, Mezzapelle R (2020) The chemokine receptor CXCR4 in cell proliferation and tissue regeneration. Front Immunol 11:2109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are thankful to the staff of the Students Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran, and also the staff of Medical Plants Research Center, Shahrekord University of Medical Sciences, Iran for their contribution and convincing comments.

Funding

This study was funded by Shahrekord University of Medical Sciences (Grant Number 2389).

Author information

Authors and Affiliations

  1. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Mohsen Shahmoradi, Fatemeh Banisharif-Dehkordi, Mahnoush kouhihabibidehkordi, Mahdi GhatrehSamani & Hedayatollah Shirzad

  2. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA

    Mohammad-Saied Jami

  3. Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Batoul Pourgheysari Ph.D.

Authors
  1. Mohsen Shahmoradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatemeh Banisharif-Dehkordi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mahnoush kouhihabibidehkordi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahdi GhatrehSamani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad-Saied Jami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hedayatollah Shirzad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Batoul Pourgheysari Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Batoul Pourgheysari Ph.D..

Ethics declarations

Conflict of interest

The authors declared that there is no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shahmoradi, M., Banisharif-Dehkordi, F., kouhihabibidehkordi, M. et al. Molecular effects of genistein, as a potential anticancer agent, on CXCR-4 and VEGF pathway in acute lymphoblastic leukemia. Mol Biol Rep 49, 4161–4170 (2022). https://doi.org/10.1007/s11033-022-07163-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-07163-0

Keywords

Search

Navigation