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Chronic Lymphocytic Leukemia

DHMEQ, a new NF-κB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells


Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. Strong and constitutive nuclear factor kappa B (NF-κB) activation is a characteristic of CLL cells. We examined the effects of a new NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on CLL cells. Dehydroxymethylepoxyquinomicin completely abrogated constitutive NF-κB activity and induced apoptosis of CLL cells. Apoptosis induced by DHMEQ was accompanied by downregulation of NF-κB-dependent antiapoptotic genes: c-IAP, Bfl-1, Bcl-XL and c-FLIP. Dehydroxymethylepoxyquinomicin also inhibited NF-κB induced by CD40 and enhanced fludarabine-mediated apoptosis of CLL cells. Results of this study suggest that inhibition of constitutive and inducible NF-κB by DHMEQ in combination with fludarabine is a promising strategy for the treatment of CLL.

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  1. Keating MJ . Chronic lymphocytic leukemia. Semin Oncol 1999; 26: 107–114.

    CAS  PubMed  Google Scholar 

  2. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91: 3379–3389.

    CAS  PubMed  Google Scholar 

  3. Griffin J . The biology of signal transduction inhibition: basic science to novel therapies. Semin Oncol 2001; 28: 3–8.

    CAS  Article  PubMed  Google Scholar 

  4. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–572.

    CAS  PubMed  Google Scholar 

  5. Capdeville R, Silberman S, Dimitrijevic S . Imatinib: the first 3 years. Eur J Cancer 2002; 38 (Suppl 5): S77–S82.

    Article  PubMed  Google Scholar 

  6. Furman RR, Asgary Z, Mascarenhas JO, Liou HC, Schattner EJ . Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol 2000; 164: 2200–2206.

    CAS  Article  PubMed  Google Scholar 

  7. Barkett M, Gilmore TD . Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6910–6924.

    CAS  Article  PubMed  Google Scholar 

  8. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin Jr AS . NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 1999; 19: 5785–5799.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Pahler JC, Ruiz S, Niemer I, Calvert LR, Andreeff M, Keating M et al. Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. Clin Cancer Res 2003; 9: 4570–4577.

    CAS  PubMed  Google Scholar 

  10. Kelley TW, Alkan S, Srkalovic G, Hsi ED . Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis. Leuk Res 2004; 28: 845–850.

    CAS  Article  PubMed  Google Scholar 

  11. Matsumoto N, Ariga A, To-e S, Nakamura H, Agata N, Hirano S et al. Synthesis of NF-kappaB activation inhibitors derived from epoxyquinomicin C. Bioorg Med Chem Lett 2000; 10: 865–869.

    CAS  Article  PubMed  Google Scholar 

  12. Ariga A, Namekawa J, Matsumoto N, Inoue J, Umezawa K . Inhibition of tumor necrosis factor-alpha-induced nuclear translocation and activation of NF-kappa B by dehydroxymethylepoxyquinomicin. J Biol Chem 2002; 277: 24625–24630.

    CAS  Article  PubMed  Google Scholar 

  13. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  14. Andrews NC, Faller DV . A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res 1991; 19: 2499.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanegae Y et al. Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin–Reed–Sternberg cells. Oncogene 2002; 21: 2493–2503.

    CAS  Article  PubMed  Google Scholar 

  16. Romano MF, Lamberti A, Tassone P, Alfinito F, Costantini S, Chiurazzi F et al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood 1998; 92: 990–995.

    CAS  PubMed  Google Scholar 

  17. Carew JS, Nawrocki ST, Krupnik YV, Dunner Jr K, McConkey DJ, Keating MJ et al. Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL. Blood 2006; 107: 222–231.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Morales AA, Olsson A, Celsing F, Osterborg A, Jondal M, Osorio LM . High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia. Int J Cancer 2005; 113: 730–737.

    CAS  Article  PubMed  Google Scholar 

  19. Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 2004; 18: 1391–1400.

    CAS  Article  PubMed  Google Scholar 

  20. Tallman MS, Hakimian D . Purine nucleoside analogs: emerging roles in indolent lymphoproliferative disorders. Blood 1995; 86: 2463–2474.

    CAS  PubMed  Google Scholar 

  21. Huang P, Sandoval A, Van Den Neste E, Keating MJ, Plunkett W . Inhibition of RNA transcription: a biochemical mechanism of action against chronic lymphocytic leukemia cells by fludarabine. Leukemia 2000; 14: 1405–1413.

    CAS  Article  PubMed  Google Scholar 

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We thank Professor Marshall E Kadin, Harvard Medical School, for critical comments on the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from Japanese Society for Promotion of Science and Integrative Research Program of the Graduate School of Medical Sciences, Kitasato University to R Horie.

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Correspondence to R Horie.

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Horie, R., Watanabe, M., Okamura, T. et al. DHMEQ, a new NF-κB inhibitor, induces apoptosis and enhances fludarabine effects on chronic lymphocytic leukemia cells. Leukemia 20, 800–806 (2006).

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  • CLL
  • NF-κB
  • apoptosis
  • fludarabine

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