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.

  • Spotlight
  • Published:

P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate

Leukemia volume 18, pages 401–408 (2004)Cite this article

Abstract

Imatinib (Glivec®, STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Tsao AS, Kantarijian H, Talpaz M . STI-571 in chronic myelogenous leukaemia. Br J Haematol 2002; 119: 15–24.

    Article  CAS  Google Scholar 

  2. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J . Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000; 289: 1938–1942.

    Article  CAS  Google Scholar 

  3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037.

    Article  CAS  Google Scholar 

  4. 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 

  5. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000; 95: 1758–1766.

    CAS  PubMed  Google Scholar 

  6. 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 

  7. von Bubnoff N, Schneller F, Peschel C, Duyster J . BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 2002; 359: 487–491.

    Article  CAS  Google Scholar 

  8. Azam M, Latek RR, Daley GQ . Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003; 112: 831–843.

    Article  CAS  Google Scholar 

  9. Roumiantsev S, Shah NP, Gorre ME, Nicoll J, Brasher BB, Sawyers CL et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci USA 2002; 99: 10700–10705.

    Article  CAS  Google Scholar 

  10. Kantarjian HM, Talpaz M, O'Brien S, Giles F, Garcia-Manero G, Faderl S et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003; 101: 473–475.

    Article  CAS  Google Scholar 

  11. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1070–1079.

    CAS  PubMed  Google Scholar 

  12. Gottesman MM, Fojo T, Bates SE . Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2: 48–58.

    Article  CAS  Google Scholar 

  13. Giles FJ, Kantarjian HM, Cortes J, Thomas DA, Talpaz M, Manshouri T et al. Multidrug resistance protein expression in chronic myeloid leukemia: associations and significance. Cancer 1999; 86: 805–813.

    Article  CAS  Google Scholar 

  14. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 2002; 62: 4955–4962.

    CAS  PubMed  Google Scholar 

  15. Lamy T, Drenou B, Grulois I, Fardel O, Jacquelinet C, Goasguen J et al. Multi-drug resistance (MDR) activity in acute leukemia determined by rhodamine 123 efflux assay. Leukemia 1995; 9: 1549–1555.

    CAS  PubMed  Google Scholar 

  16. Bierhaus A, Illmer T, Kasper M, Luther T, Quehenberger P, Tritschler H et al. Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE. Circulation 1997; 96: 2262–2271.

    Article  CAS  Google Scholar 

  17. Yu C, Krystal G, Varticovksi L, McKinstry R, Rahmani M, Dent P et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res 2002; 62: 188–199.

    CAS  PubMed  Google Scholar 

  18. List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 2001; 98: 3212–3220.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  20. Hofmann WK, de Vos S, Elashoff D, Gschaidmeier H, Hoelzer D, Koeffler HP et al. Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet 2002; 359: 481–486.

    Article  CAS  Google Scholar 

  21. Warmuth M, Simon N, Mitina O, Mathes R, Fabbro D, Manley PW et al. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood 2003; 101: 664–672.

    Article  CAS  Google Scholar 

  22. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101: 690–698.

    Article  CAS  Google Scholar 

  23. List AF . Role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. Leukemia 1996; 10: 937–942.

    CAS  PubMed  Google Scholar 

  24. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003; 101: 2368–2373.

    Article  CAS  Google Scholar 

  25. List AF, Kopecky KJ, Willman CL, Head DR, Slovak ML, Douer D et al. Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase. Blood 2002; 100: 1910–1912.

    CAS  PubMed  Google Scholar 

  26. Mickley LA, Spengler BA, Knutsen TA, Biedler JL, Fojo T . Gene rearrangement: a novel mechanism for MDR-1 gene activation. J Clin Invest 1997; 99: 1947–1957.

    Article  CAS  Google Scholar 

  27. Brummendorf TH, Ersoz I, Hartmann U, Bartolovic K, Balabanov S, Wahl A et al. Telomere length in peripheral blood granulocytes reflects response to treatment with imatinib in patients with chronic myeloid leukemia. Blood 2003; 101: 375–376.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are very grateful for the excellent technical assistance of Edith Harbig-Brutscher and Anja Liebkopf.

Author information

Authors and Affiliations

  1. Medical Clinic and Policlinic I, University Hospital of the Technical University, Dresden, Germany

    T Illmer, M Schaich, U Platzbecker, J Freiberg-Richter, U Oelschlägel, M von Bonin, S Pursche, T Bergemann, G Ehninger & E Schleyer

Authors
  1. T Illmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Schaich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U Platzbecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Freiberg-Richter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U Oelschlägel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M von Bonin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Pursche
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Bergemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Ehninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Schleyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Illmer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Illmer, T., Schaich, M., Platzbecker, U. et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 18, 401–408 (2004). https://doi.org/10.1038/sj.leu.2403257

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403257

Keywords

This article is cited by

Search

Advanced search

Quick links