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CLL

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells

Leukemia volume 19, pages 64–68 (2005)Cite this article

Abstract

Fludarabine is considered the treatment of choice for most patients with chronic lymphocytic leukemia (CLL). We have analyzed the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in CLL cells. Among the known plasma membrane transporters, we have previously observed a significant correlation between fludarabine uptake via ENT carriers and ex vivo sensitivity of CLL cells to fludarabine, although mRNA amounts of the equilibrative nucleoside transporters hENT1 and hENT2 do not show any predictive response to treatment. In this study, using polyclonal monospecific antibodies we have observed a significant correlation between the expression of hENT2 by Western blot and fludarabine uptake via hENT carriers and also with ex vivo sensitivity of CLL cells to fludarabine. These results suggest that the equilibrative nucleoside transporter hENT2 plays a role in fludarabine responsiveness in CLL patients.

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References

  1. Kipps TJ . Immunobiology of chronic lymphocytic leukemia. Curr Opin Hematol 2003; 10: 312–318.

    Article  PubMed  Google Scholar 

  2. Reed JC . Molecular biology of chronic lymphocytic leukemia. Semin Oncol 1998; 25: 11–18.

    CAS  PubMed  Google Scholar 

  3. Robak T, Kasznicki M . Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia. Leukemia 2002; 16: 1015–1027.

    Article  CAS  PubMed  Google Scholar 

  4. Bellosillo B, Villamor N, Colomer D, Pons G, Montserrat E, Gil J . In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood 1999; 94: 2836–2843.

    CAS  PubMed  Google Scholar 

  5. Carrera CJ, Piro LD, Saven A, Beutler E, Terai C, Carson DA . 2-Chlorodeoxyadenosine chemotherapy triggers programmed cell death in normal and malignant lymphocytes. Adv Exp Med Biol 1991; 309A: 15–18.

    Article  CAS  PubMed  Google Scholar 

  6. Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB . Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine. Proc Natl Acad Sci USA 1992; 89: 2970–2974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Reed JC, Kitada S, Kim Y, Byrd J . Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. Semin Oncol 2002; 29: 10–24.

    Article  CAS  PubMed  Google Scholar 

  8. Robertson LE, Chubb S, Meyn RE, Story M, Ford R, Hittelman WN et al. Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-2′-deoxyadenosine and 9-beta-D-arabinosyl-2-fluoroadenine. Blood 1993; 81: 143–150.

    CAS  PubMed  Google Scholar 

  9. Zinzani PL, Tosi P, Visani G, Martinelli G, Farabegoli P, Buzzi M et al. Apoptosis induction with three nucleoside analogs on freshly isolated B-chronic lymphocytic leukemia cells. Am J Hematol 1994; 47: 301–306.

    Article  CAS  PubMed  Google Scholar 

  10. Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB et al. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 2000; 96: 3537–3543.

    CAS  PubMed  Google Scholar 

  11. Sturm I, Bosanquet AG, Hermann S, Guner D, Dorken B, Daniel PT . Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ 2003; 10: 477–484.

    Article  CAS  PubMed  Google Scholar 

  12. Dumontet C, Fabianowska-Majewska K, Mantincic D, Callet BE, Tigaud I, Gandhi V et al. Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br J Haematol 1999; 106: 78–85.

    Article  CAS  PubMed  Google Scholar 

  13. Galmarini CM, Mackey JR, Dumontet C . Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 2001; 15: 875–890.

    Article  CAS  PubMed  Google Scholar 

  14. Galmarini CM, Jordheim L, Dumontet C . Role of IMP-selective 5′-nucleotidase (cN-II) in hematological malignancies. Leuk Lymphoma 2003; 44: 1105–1111.

    Article  CAS  PubMed  Google Scholar 

  15. Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD . The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 2004; 447: 735–743.

    Article  CAS  PubMed  Google Scholar 

  16. Gray JH, Owen RP, Giacomini KM . The concentrative nucleoside transporter family, SLC28. Pflugers Arch 2004; 447: 728–734.

    Article  CAS  PubMed  Google Scholar 

  17. Pastor-Anglada M, Molina-Arcas M, Casado FJ, Bellosillo B, Colomer D, Gil J . Nucleoside transporters in chronic lymphocytic leukaemia. Leukemia 2004; 18: 385–393.

    Article  CAS  PubMed  Google Scholar 

  18. Molina-Arcas M, Bellosillo B, Casado FJ, Montserrat E, Gil J, Colomer D et al. Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Blood 2003; 101: 2328–2334.

    Article  CAS  PubMed  Google Scholar 

  19. Farre X, Guillen-Gomez E, Sanchez L, Hardisson D, Plaza Y, Lloberas J et al. Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Int J Cancer 2004; 112: 959–966.

    Article  CAS  PubMed  Google Scholar 

  20. Mackey JR, Jennings LL, Clarke ML, Santos CL, Dabbagh L, Vsianska M et al. Immunohistochemical variation of human equilibrative nucleoside transporter 1 protein in primary breast cancers. Clin Cancer Res 2002; 8: 110–116.

    CAS  PubMed  Google Scholar 

  21. Galmarini CM, Thomas X, Calvo F, Rousselot P, Rabilloud M, El Jaffari A et al. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br J Haematol 2002; 117: 860–868.

    Article  CAS  PubMed  Google Scholar 

  22. Jaffe ES, Harris NL, Stein H, Vardiman JW (ed). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, 2001, IARC Press: Lyon, 168–170.

  23. Colomer D, Vives Corrons JL, Bartrons R . Effect of TPA on fructose 2,6-bisphosphate levels and protein kinase C activity in B-chronic lymphocytic leukemia (B-CLL). Biochim Biophys Acta 1991; 1097: 270–274.

    Article  CAS  PubMed  Google Scholar 

  24. Valdes R, Ortega MA, Casado FJ, Felipe A, Gil A, Sanchez-Pozo A et al. Nutritional regulation of nucleoside transporter expression in rat small intestine. Gastroenterology 2000; 119: 1623–1630.

    Article  CAS  PubMed  Google Scholar 

  25. Alessi-Severini S, Gati WP, Belch AR, Paterson AR . Intracellular pharmacokinetics of 2-chlorodeoxyadenosine in leukemia cells from patients with chronic lymphocytic leukemia. Leukemia 1995; 9: 1674–1679.

    CAS  PubMed  Google Scholar 

  26. Wright AM, Gati WP, Paterson AR . Enhancement of retention and cytotoxicity of 2-chlorodeoxyadenosine in cultured human leukemic lymphoblasts by nitrobenzylthioinosine, an inhibitor of equilibrative nucleoside transport. Leukemia 2000; 14: 52–60.

    Article  CAS  PubMed  Google Scholar 

  27. Campas C, Lopez JM, Santidrian AF, Barragan M, Bellosillo B, Colomer D, Gil J . Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Blood 2003; 101: 3674–3680.

    Article  CAS  PubMed  Google Scholar 

  28. Gati WP, Paterson AR, Larratt LM, Turner AR, Belch AR . Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein. Blood 1997; 90: 346–353.

    CAS  PubMed  Google Scholar 

  29. Aguayo C, Casado FJ, Pastor-Anglada M, Sobrevia L . Effect of hyperglycaemia on cellular localization of human equilibrative nucleoside transporters (hENT) in umbilical vein endothelial cells. J Physiol 2001, 536p.

  30. Lai Y, Tse CM, Unadkat JD . Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs. J Biol Chem 2004; 279: 4490–4497.

    Article  CAS  PubMed  Google Scholar 

  31. Coe I, Zhang Y, McKenzie T, Naydenova Z . PKC regulation of the human equilibrative nucleoside transporter, hENT1. FEBS Lett 2002; 517: 201–205.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by Grant SAF2002-0717 (Ministerio de Ciencia y Tecnología, Spain) and a Grant-in-Aid from Fundación Ramón Areces (Spain) to MP-A, and Grant 03-0398 (Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo, Spain) to DC. MM-A was an AECC fellow and now holds a research fellowship from the Ministerio de Educación, Cultura y Deportes, Spain.

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Author notes

  1. B Bellosillo

    Present address: Servei de Patologia, Hospital del Mar, Barcelona, Spain

  2. M Molina-Arcas and S Marcé: These two authors contributed equally to this study

Authors and Affiliations

  1. Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain

    M Molina-Arcas, I Huber-Ruano, F J Casado & M Pastor-Anglada

  2. Unitat d'Hematopatologia, Hospital Clínic, IDIBAPS, Barcelona, Spain

    S Marcé, N Villamor, B Bellosillo & D Colomer

  3. Servei d'Hematologia, Hospital Clínic, IDIBAPS, Barcelona, Spain

    E Montserrat

  4. Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, Hospitalet, Spain

    J Gil

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  1. M Molina-Arcas
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Correspondence to M Pastor-Anglada.

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Molina-Arcas, M., Marcé, S., Villamor, N. et al. Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells. Leukemia 19, 64–68 (2005). https://doi.org/10.1038/sj.leu.2403582

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