Cancer Immunology, Immunotherapy

, Volume 61, Issue 12, pp 2321–2331 | Cite as

EGCG targeting efficacy of NF-κB downstream gene products is dictated by the monocytic/macrophagic differentiation status of promyelocytic leukemia cells

Original article

Abstract

Central nervous system infiltration by circulating leukemic cells and enhanced in vitro transendothelial migration of promyelocytic leukemia HL-60-derived macrophages through a blood–brain barrier model was recently demonstrated. The intrinsic molecular and signaling mechanisms involved are, however, poorly documented. Drug targeting of such translocation event performed by circulating microbes and immune cells may prevent secondary cerebral infections and development of brain pathologies. In this study, we specifically investigated the in vitro targeting efficacy of the chemopreventive and dietary-derived epigallocatechin-3-gallate (EGCG) molecule on the NF-κB-mediated transcriptional regulation of a panel of 89 biomarkers associated with promyelocytic HL-60 differentiation into macrophages. NF-κB-mediated signaling during HL-60 macrophage differentiation was reversed by EGCG, in part through reduced IκB phosphorylation and led to the inhibition of moderately to highly expressed NF-κB gene targets among which the matrix metalloproteinase (MMP)-9 and the cyclooxygenase (COX)-2. In contrast, EGCG exhibited low efficacy in reversing NF-κB-regulated genes and showed selective antagonism toward COX-2 expression while that of MMP-9 remained high in terminally differentiated macrophages. Decreased expression of the 67-kDa non-integrin Laminin Receptor in terminally differentiated macrophages may explain such differential EGCG efficacy. Our results suggest that terminally differentiated macrophage transendothelial migration associated with neuroinflammation may not be pharmacologically affected by such a specific class of flavonoid. The differentiation status of a given in vitro cell model must therefore be carefully considered for optimized assessment of therapeutic drugs.

Keywords

EGCG Leukemia NF-κB Macrophage differentiation Blood–brain barrier 

Abbreviations

BBB

Blood–brain barrier

ECM

Extracellular matrix

EGCG

Epigallocatechin-3-gallate

LR

Laminin receptor

MMP-9

Matrix metalloproteinase-9

NF-κB

Nuclear factor-kappa B

PMA

Phorbol 12-myristate 13-acetate

Notes

Acknowledgments

BA holds a Canada Research Chair in Molecular Oncology from the Canadian Institutes of Health Research (CIHR). This study was funded by a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC).

Conflict of interest

The authors declare no conflict or competing financial interest.

References

  1. 1.
    Zhu Z, Zhong S, Shen Z (2011) Targeting the inflammatory pathways to enhance chemotherapy of cancer. Cancer Biol Ther 12(2):95–105PubMedCrossRefGoogle Scholar
  2. 2.
    Cilloni D, Martinelli G, Messa F et al (2007) Nuclear factor kB as a target for new drug development in myeloid malignancies. Haematologica 92(9):1224–1229PubMedCrossRefGoogle Scholar
  3. 3.
    Breccia M, Alimena G (2010) NF-κB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia. Expert Opin Ther Targets 14(11):1157–1176PubMedCrossRefGoogle Scholar
  4. 4.
    Pepper C, Hewamana S, Brennan P et al (2009) NF-kappaB as a prognostic marker and therapeutic target in chronic lymphocytic leukemia. Future Oncol 5(7):1027–1037PubMedCrossRefGoogle Scholar
  5. 5.
    Fuchs O (2010) Transcription factor NF-κB inhibitors as single therapeutic agents or in combination with classical chemotherapeutic agents for the treatment of hematologic malignancies. Curr Mol Pharmacol 3(3):98–122PubMedGoogle Scholar
  6. 6.
    Larson RA, Daley GQ, Schiffer CA et al (2003) Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002. Leukemia 17(12):2358–2382PubMedCrossRefGoogle Scholar
  7. 7.
    Park JH, Tallman MS (2011) Treatment of acute promyelocytic leukemia without cytotoxic chemotherapy. Oncology (Williston Park) 25(8):733–741Google Scholar
  8. 8.
    Surh Y (1999) Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 428(1–2):305–327PubMedGoogle Scholar
  9. 9.
    Yang H, Landis-Piwowar KH, Chan T et al (2011) Green tea polyphenols as proteasome inhibitors: implication in chemoprevention. Curr Cancer Drug Targets 11(3):296–306PubMedCrossRefGoogle Scholar
  10. 10.
    Khan N, Afaq F, Saleem M et al (2006) Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate. Cancer Res 66(5):2500–2505PubMedCrossRefGoogle Scholar
  11. 11.
    Mereles D, Hunstein W (2011) Epigallocatechin-3-gallate (EGCG) for clinical trials: more pitfalls than promises? Int J Mol Sci 12(9):5592–5603PubMedCrossRefGoogle Scholar
  12. 12.
    Na HK, Surh YJ (2006) Intracellular signaling network as a prime chemopreventive target of (-)-epigallocatechin gallate. Mol Nutr Food Res 50(2):152–159PubMedCrossRefGoogle Scholar
  13. 13.
    Demeule M, Michaud-Levesque J, Annabi B et al (2002) Green tea catechins as novel antitumor and antiangiogenic compounds. Curr Med Chem Anticancer Agents 2(4):441–463PubMedCrossRefGoogle Scholar
  14. 14.
    Thomas DA, Giles FJ, Cortes J et al (2001) Antiangiogenic therapy in leukemia. Acta Haematol 106(4):190–207PubMedCrossRefGoogle Scholar
  15. 15.
    Moehler TM, Hillengass J, Goldschmidt H et al (2004) Antiangiogenic therapy in hematologic malignancies. Curr Pharm Des 10(11):1221–1234PubMedCrossRefGoogle Scholar
  16. 16.
    Collins SJ, Ruscetti FW, Gallagher RE et al (1978) Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc Natl Acad Sci USA 75(5):2458–2462PubMedCrossRefGoogle Scholar
  17. 17.
    Huberman E, Callaham MF (1979) Induction of terminal differentiation in human promyelocytic leukemia cells by tumor-promoting agents. Proc Natl Acad Sci USA 76(3):1293–1297PubMedCrossRefGoogle Scholar
  18. 18.
    Tonetti DA, Henning-Chubb C, Yamanishi DT et al (1994) Protein kinase C-beta is required for macrophage differentiation of human HL-60 leukemia cells. J Biol Chem 269(37):23230–23235PubMedGoogle Scholar
  19. 19.
    Xie B, Laouar A, Huberman E (1998) Autocrine regulation of macrophage differentiation and 92-kDa gelatinase production by tumor necrosis factor-alpha via alpha5 beta1 integrin in HL-60 cells. J Biol Chem 273(19):11583–11588PubMedCrossRefGoogle Scholar
  20. 20.
    McMillan JI, Weeks R, West JW et al (1996) Pharmacological inhibition of gelatinase B induction and tumor cell invasion. Int J Cancer 67(4):523–531PubMedCrossRefGoogle Scholar
  21. 21.
    Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196(3):254–265PubMedCrossRefGoogle Scholar
  22. 22.
    D’Alessandro T, Prasain J, Benton MR et al (2003) Polyphenols, inflammatory response, and cancer prevention: chlorination of isoflavones by human neutrophils. J Nutr 133(11 Suppl 1):3773S–3777SPubMedGoogle Scholar
  23. 23.
    Belkaid A, Fortier S, Cao J et al (2007) Necrosis induction in glioblastoma cells reveals a new “bioswitch” function for the MT1-MMP/G6PT signaling axis in proMMP-2 activation versus cell death decision. Neoplasia 9(4):332–340PubMedCrossRefGoogle Scholar
  24. 24.
    Annabi B, Currie JC, Moghrabi A et al (2007) Inhibition of HuR and MMP-9 expression in macrophage-differentiated HL-60 myeloid leukemia cells by green tea polyphenol EGCg. Leuk Res 31(9):1277–1284PubMedCrossRefGoogle Scholar
  25. 25.
    Jin R, Yang G, Li G (2010) Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis 38(3):376–385PubMedCrossRefGoogle Scholar
  26. 26.
    Candelario-Jalil E, Taheri S, Yang Y et al (2007) Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther 323(2):488–498PubMedCrossRefGoogle Scholar
  27. 27.
    Umeda D, Yano S, Yamada K et al (2008) Green tea polyphenol epigallocatechin-3-gallate signaling pathway through 67-kDa laminin receptor. J Biol Chem 283(6):3050–3058PubMedCrossRefGoogle Scholar
  28. 28.
    Arkan MC, Greten FR (2011) IKK- and NF-κB-mediated functions in carcinogenesis. Curr Top Microbiol Immunol 349:159–169PubMedCrossRefGoogle Scholar
  29. 29.
    Cabrini G, Bezzerri V, Mancini I et al (2010) Targeting transcription factor activity as a strategy to inhibit pro-inflammatory genes involved in cystic fibrosis: decoy oligonucleotides and low-molecular weight compounds. Curr Med Chem 17(35):4392–4404PubMedCrossRefGoogle Scholar
  30. 30.
    Bamborough P, Morse MA, Ray KP (2010) Targeting IKKβ for the treatment of rheumatoid arthritis. Drug News Perspect 23(8):483–490PubMedGoogle Scholar
  31. 31.
    Chen S (2011) Natural products triggering biological targets—a review of the anti-inflammatory phytochemicals targeting the arachidonic acid pathway in allergy asthma and rheumatoid arthritis. Curr Drug Targets 12(3):288–301PubMedCrossRefGoogle Scholar
  32. 32.
    Chen W, Li Z, Bai L et al (2011) NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front Biosci 16:1172–1185PubMedCrossRefGoogle Scholar
  33. 33.
    Adams H, Obermann EC, Dirnhofer S et al (2011) Targetable molecular pathways in classical Hodgkin’s lymphoma. Expert Opin Investig Drugs 20(2):141–151PubMedCrossRefGoogle Scholar
  34. 34.
    Prasad S, Phromnoi K, Yadav VR et al (2010) Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Med 76(11):1044–1063PubMedCrossRefGoogle Scholar
  35. 35.
    Luqman S, Pezzuto JM (2010) NFkappaB: a promising target for natural products in cancer chemoprevention. Phytother Res 24(7):949–963PubMedGoogle Scholar
  36. 36.
    Baud V, Karin M (2009) Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 8(1):33–40PubMedCrossRefGoogle Scholar
  37. 37.
    Ono M (2008) Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 99(8):1501–1506PubMedCrossRefGoogle Scholar
  38. 38.
    Hazawa M, Takahashi K, Sugata S et al (2011) (-)-Epigallocatechin-3-O-gallate induces nonapoptotic cell death in leukemia cells independent of the 67 kDa laminin receptor. J Nat Prod 74(4):695–700PubMedCrossRefGoogle Scholar
  39. 39.
    Tergaonkar V (2006) NFkappaB pathway: a good signaling paradigm and therapeutic target. Int J Biochem Cell Biol 38(10):1647–1653PubMedCrossRefGoogle Scholar
  40. 40.
    Lakka SS, Gondi CS, Rao JS (2005) Proteases and glioma angiogenesis. Brain Pathol 15(4):327–341PubMedCrossRefGoogle Scholar
  41. 41.
    Bonoiu A, Mahajan SD, Ye L et al (2009) MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier. Brain Res 1282:142–155PubMedCrossRefGoogle Scholar
  42. 42.
    Lambert JD, Yang CS (2003) Mechanisms of cancer prevention by tea constituents. J Nutr 133(10):3262S–3267SPubMedGoogle Scholar
  43. 43.
    Demeule M, Brossard M, Pagé M et al (2000) Matrix metalloproteinase inhibition by green tea catechins. Biochim Biophys Acta 1478(1):51–60PubMedCrossRefGoogle Scholar
  44. 44.
    Craggs L, Kalaria RN (2011) Revisiting dietary antioxidants, neurodegeneration and dementia. NeuroReport 22(1):1–3PubMedCrossRefGoogle Scholar
  45. 45.
    Akool el S, Kleinert H, Hamada FM et al (2003) Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Mol Cell Biol 23(14):4901–4916CrossRefGoogle Scholar
  46. 46.
    Johann AM, Weigert A, Eberhardt W et al (2008) Apoptotic cell-derived sphingosine-1-phosphate promotes HuR-dependent cyclooxygenase-2 mRNA stabilization and protein expression. J Immunol 180(2):1239–1248PubMedGoogle Scholar
  47. 47.
    Rusak G, Gutzeit HO, Ludwig-Műller J (2005) Structurally related flavonoids with antioxidative properties differentially affect cell cycle progression and apoptosis of human acute leukemia cells. Nutr Res 25(2):143–155CrossRefGoogle Scholar
  48. 48.
    Rice-Evans C, Packer L (eds) (2003) Flavonoids in health and disease, 2nd edn. Marcel Dekker Inc., New YorkGoogle Scholar
  49. 49.
    Tahanian E, Sanchez LA, Shiao TC et al (2011) Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells. Drug Des Devel Ther 5:299–309PubMedGoogle Scholar
  50. 50.
    Williams P, Sorribas A, Howes MJ (2011) Natural products as a source of Alzheimer’s drug leads. Nat Prod Rep 28(1):48–77PubMedCrossRefGoogle Scholar
  51. 51.
    Howes MJ, Perry E (2011) The role of phytochemicals in the treatment and prevention of dementia. Drugs Aging 28(6):439–468PubMedCrossRefGoogle Scholar
  52. 52.
    Feng SR, Chen ZX, Cen JN et al (2011) Disruption of blood brain-barrier by leukemic cells in central nervous system leukemia. Zhonghua Xue Ye Xue Za Zhi 32(5):289–293PubMedGoogle Scholar
  53. 53.
    Feng S, Cen J, Huang Y et al (2011) Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS ONE 6(8):e20599PubMedCrossRefGoogle Scholar
  54. 54.
    Seidel G, Böcker K, Schulte J et al (2011) Pertussis toxin permeabilization enhances the traversal of Escherichia coli K1, macrophages, and monocytes in a cerebral endothelial barrier model in vitro. Int J Med Microbiol 301(3):204–212PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Laboratoire d’Oncologie Moléculaire, Département de Chimie, Centre de Recherche BioMEDUniversité du Québec à MontréalMontréalCanada
  2. 2.Département de PhysiologieUniversité de MontréalQuébecCanada

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