Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Myeloid Leukemia, BCR/ABL Studies and Myeloproliferative Disorders

The NF-κB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance

Leukemia volume 20, pages 61–67 (2006)Cite this article

Abstract

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-κB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-κB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.

    Article  CAS  Google Scholar 

  2. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.

    Article  CAS  Google Scholar 

  3. Kantarjian HM, Cortes JE, O'Brien S, Giles F, Garcia-Manero G, Faderl S et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood 2003; 101: 97–100.

    Article  CAS  Google Scholar 

  4. Kantarjian HM, Cortes J, O'Brien S, Giles FJ, Albitar M, Rios MB et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002; 99: 3547–3553.

    Article  CAS  Google Scholar 

  5. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042.

    Article  CAS  Google Scholar 

  6. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L . Molecular mechanism of resistance to Imatinib in Philadelphia-chromosome-positive leukemias. Lancet Oncol 2003; 4: 75–85.

    Article  Google Scholar 

  7. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  Google Scholar 

  8. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003; 102: 276–283.

    Article  CAS  Google Scholar 

  9. Ghosh S, Karin M . Missing pieces in the NF-κB puzzle. Cell 2002; 109: 81–96.

    Article  Google Scholar 

  10. Lin A, Karin M . NF-κB in cancer: a merked target. Semin Cancer Biol 2003; 13: 107–114.

    Article  CAS  Google Scholar 

  11. Garg A, Aggarwal BB . Nuclear transcription factor-kB as a target for cancer drug development. Leukemia 2002; 16: 1053–1068.

    Article  CAS  Google Scholar 

  12. Turco MC, Romano MF, Petrella A, Bisogni R, Tassone P, Venuta S . NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors. Leukemia 2003; 18: 1–7.

    Google Scholar 

  13. Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 2001; 98: 2301–2307.

    Article  CAS  Google Scholar 

  14. Bueso-Ramos CE, Rocha FC, Shishodia S, Medeiros LJ, Kantarjian HM, Vadhan-Raj S et al. Expression of constitutively active nuclear-kappa B RelA transcription factor in blasts of acute myeloid leukemia. Hum Pathol 2004; 35: 246–253.

    Article  CAS  Google Scholar 

  15. Baumgartner B, Weber M, Quirling M, Fischer C, Page S, Adam M et al. Increased IkappaB kinase activity is associated with activated NF-kappaB in acute myeloid blasts. Leukemia 2002; 16: 2062–2071.

    Article  CAS  Google Scholar 

  16. Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C . Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 2000; 3: 399–402.

    Article  Google Scholar 

  17. Bailly JD, Skladanowski A, Bettaieb A, Mansat V, Larsen AK, Laurent G . Natural resistance of acute myeloid leukemia cell lines to mitoxantrone is associated with lack of apoptosis. Leukemia 1997; 9: 1523–1532.

    Article  Google Scholar 

  18. Panwalkar A, Verstovsek S, Giles F . Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies. Cancer 2004; 15: 1578–1589.

    Article  Google Scholar 

  19. Umezawa K, Chaicharoenpong C . Molecular design and biological activities of NF-kappaB inhibitors. Mol Cells 2002; 14: 163–167.

    CAS  PubMed  Google Scholar 

  20. Karin M, Ben-Neriah Y . Phosphorilation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000; 18: 621–663.

    Article  CAS  Google Scholar 

  21. Karin M, Lin A . NF-κB at the crossroads of life and death. Nat Immunol 2002; 3: 221–227.

    Article  CAS  Google Scholar 

  22. Senftleben U, Karin M . The IKK/NF-κB pathway. Crit Care Med 2002; 30: 18–26.

    Article  Google Scholar 

  23. Hayashi T, Hideshima T, Anderson KC . Novel therapies for multiple myeloma. Br J Haematol 2003; 120: 10–17.

    Article  CAS  Google Scholar 

  24. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639–16647.

    Article  CAS  Google Scholar 

  25. Cilloni D, Carlo-Stella C, Falzetti F, Sammarelli G, Regazzi E, Colla S et al. Limited engraftment capacity of bone marrow-derived mesenchymal cells following T cell depleted hematopoietic stem cell transplantation. Blood 2000; 96: 3637–3643.

    CAS  PubMed  Google Scholar 

  26. Aradhya S, Nelson DL . NF-κB signaling and human disease. Curr Opin Genet Dev 2000; 11: 300–306.

    Article  Google Scholar 

  27. Pahl HL . Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6853–6866.

    Article  CAS  Google Scholar 

  28. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M et al. The IKK beta subunit of I kappa B kinase B kinase (IKK) is essential for nuclear factor kappa B activatation and prevention of apoptosis. J Exp Med 1999; 189: 1839–1845.

    Article  CAS  Google Scholar 

  29. Zandi E, Chen Y, Karin M . Direct phosphorilation of IKappaB by IKKalpha and IKK beta: Discrimination between free and NF-κB bound substrate. Science 1998; 281: 1360–1363.

    Article  CAS  Google Scholar 

  30. Delhase M, Hayakawa M, Chen Y, Karin M . Positive and negative regulation of I kappa B kinase activity through IKK beta subunit phosphorylation. Science 1999; 284: 309–313.

    Article  CAS  Google Scholar 

  31. Kavai H, Nie L, Yuan ZM . Inactivation of NF-κB dependent cell survival, a novel mechanisn for the proapoptotic function of c-ABL. Mol Cell Biol 2002; 22: 6079–6088.

    Article  Google Scholar 

  32. Shaul Y . c-ABL:activation and nuclear targets. Cell Death Differ 2000; 7: 10–16.

    Article  CAS  Google Scholar 

  33. Pendergast AM . The Abl family kinases: mechanism of regulation and signaling. Adv Cancer Res 2002; 85: 51–100.

    Article  CAS  Google Scholar 

  34. Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS . A requirement for NF-κB activation in BCR-ABL mediated transformation. Genes Dev 1998; 12: 968–981.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Grants and financial support: This work has been supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro), CNR (Progetto Finalizzato Oncologia), MURST-COFIN 2003, AIL (Associazione Italiana contro le Leucemie), and by Regione Piemonte. We are indebted to Lami Oyewumi for the revision of the manuscript.

Author information

Authors and Affiliations

  1. Division of Hematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy

    D Cilloni, F Messa, F Arruga, I Defilippi, A Morotti, E Messa, S Carturan, E Giugliano, M Pautasso, V Rosso & G Saglio

  2. Department of Clinical and Biological Sciences of the University of Turin, Section of Cell Biology, Turin, Italy

    E Bracco

  3. Millennium Pharmaceuticals, Cambridge, MA, USA

    A Sen

  4. Institute of Hematology and Medical Oncology ‘L and A Seràgnoli’, University of Bologna, Bologna, Italy

    G Martinelli & M Baccarani

Authors
  1. D Cilloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Messa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Arruga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Defilippi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Morotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Messa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Carturan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Giugliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Pautasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Bracco
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. V Rosso
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Sen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Baccarani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. G Saglio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Cilloni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cilloni, D., Messa, F., Arruga, F. et al. The NF-κB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance. Leukemia 20, 61–67 (2006). https://doi.org/10.1038/sj.leu.2403998

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403998

Keywords

This article is cited by

Search

Advanced search

Quick links