Advertisement

Biochemistry (Moscow)

, Volume 73, Issue 1, pp 29–37 | Cite as

Role of P-glycoprotein in evolution of populations of chronic myeloid leukemia cells treated with imatinib

  • T. P. StromskayaEmail author
  • E. Yu. Rybalkina
  • S. S. Kruglov
  • T. N. Zabotina
  • E. B. Mechetner
  • A. G. Turkina
  • A. A. Stavrovskaya
Article

Abstract

Imatinib mesylate (imatinib) is a new generation preparation that is now successfully used for treatment of cancer, particularly for chemotherapy of chronic myeloid leukemia (CML). Imatinib inhibits the activity of chimeric kinase BCR-ABL, which is responsible for the development of CML. The goal of this study was to investigate the role of a multidrug resistance protein, P-glycoprotein (Pgp), in the evolution of CML treated with imatinib. We demonstrate here that although imatinib is a substrate for Pgp, cultured CML cells (strain K562/i-S9), overexpressing active Pgp, do not exhibit imatinib resistance. Studies of CML patients in the accelerated phase have shown variations in the number of Pgp-positive cells (Pgp+) among individual patients treated with imatinib. During treatment of patients with imatinib for 6–12 months, the number of Pgp-positive cells significantly increased in most patients. The high number of Pgp+ cells remained in patients at least for 4.5 years and correlated with active Rhodamine 123 (Rh123) efflux. Such correlation was not found in the group of imatinib-resistant patients examined 35–60 months after onset of imatinib therapy: cells from the imatinibresistant patients exhibited efficient Rh123 efflux irrespectively of Pgp expression. We also compared the mode of Rh123 efflux by cells from CML patients who underwent imatinib treatment for 6–24 months and the responsiveness of patients to this therapy. There were significant differences in survival of patients depending on the absence or the presence of Rh123 efflux. In addition to Pgp, patients’ cells expressed other transport proteins of the ABC family. Our data suggest that treatment with imatinib causes selection of leukemic stem cells characterized by expression of Pgp and other ABC transporters.

Key words

P-glycoprotein chronic myeloid leukemia imatinib tyrosine kinase inhibitor BCR-ABL 

Abbreviations

AB

antibodies

AP

accelerated phase

CCR

complete cytogenetic response

CML

chronic myeloid leukemia

CR

cytogenetic response

MDR

multidrug resistance

Pgp

P-glycoprotein

Rh123

Rhodamine 123

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gschwind, A., Fischer, O. M., and Ullrich, A. (2004) Nat. Rev. Cancer, 4, 361–370.CrossRefPubMedGoogle Scholar
  2. 2.
    Faivre, S., Djelloul, S., and Raymond, E. (2006) Semin. Oncol., 33, 407–420.CrossRefPubMedGoogle Scholar
  3. 3.
    Faderl, S., Talpaz, M., Estrov, Z., and Kantarjian, H. M. (1999) Ann. Intern. Med., 131, 207–219.PubMedGoogle Scholar
  4. 4.
    Deininger, M., Buchdunger, E., and Druker, B. J. (2005) Blood, 105, 2640–2653.CrossRefPubMedGoogle Scholar
  5. 5.
    Daub, H., Specht, K., and Ullrich, A. (2004) Nat. Rev. Drug Discov., 3, 1001–1010.CrossRefPubMedGoogle Scholar
  6. 6.
    Martinelli, G., Soverini, S., Rosti, G., Cilloni, D., and Baccarani, M. (2005) Haematologica, 90, 534–541.PubMedGoogle Scholar
  7. 7.
    Stavrovskaya, A. A. (2003) Biol. Membr. (Moscow), 20, 196–205.Google Scholar
  8. 8.
    Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., and Gottesman, M. M. (2006) Nat. Rev. Drug Discov., 5, 219–234.CrossRefPubMedGoogle Scholar
  9. 9.
    Juliano, R. L., and Ling, V. (1976) Biochim. Biophys. Acta, 11, 152–162.Google Scholar
  10. 10.
    Stavrovskaya, A. A. (2000) Biochemistry (Moscow), 65, 95–106.Google Scholar
  11. 11.
    Vaiman, A. V., Stromskaya, T. P., Rybalkina, E. Yu., Sorokin, A. V., Guryanov, S. G., Zabotina, T. N., Mechetner, E. B., Ovchinnikov, L. P., and Stavrovskaya, A. A. (2006) Biochemistry (Moscow), 71, 146–154.CrossRefGoogle Scholar
  12. 12.
    Hegedus, T., Orfi, L., Seprodi, A., Varadi, A., Sarkadi, B., and Keri, G. (2002) Biochim. Biophys. Acta, 1587, 318–325.PubMedGoogle Scholar
  13. 13.
    Illmer, T., Schaich, M., Platzbecker U., Freiberg-Richter, J., Oelschlagel, U., von Bonin, M., Pursche, S., Bergemann, T., Ehninger, G., and Schleyer, E. (2004) Leukemia, 18, 401–408.CrossRefPubMedGoogle Scholar
  14. 14.
    Mukai, M., Che, X. F., Furukawa, T., Sumizawa, T., Aoki, S., Ren, X. Q., Haraguchi, M., Sugimoto, Y., Kobayashi, M., Takamatsu, H., and Akiyama, S. (2003) Cancer Sci., 94, 557–563.CrossRefPubMedGoogle Scholar
  15. 15.
    Rumpold, H., Wolf, A. M., Gruenewald, K., Gastl, G., Gunsilius, E., and Wolf, D. (2005) Exp. Hematol., 33, 767–775.CrossRefPubMedGoogle Scholar
  16. 16.
    Mahon, F. X., Belloc, F., Lagarde, V., Chollet, C., Moreau-Gaudry, F., Reiffers, J., Goldman, J. M., and Melo, J. V. (2003) Blood, 101, 2368–2373.CrossRefPubMedGoogle Scholar
  17. 17.
    Ferrao, P. T., Frost, M. J., Siah, S. P., and Ashman, L. K. (2003) Blood, 102, 4499–4503.CrossRefPubMedGoogle Scholar
  18. 18.
    Zong, Y., Zhou, S., and Sorrentino, B. P. (2005) Leukemia, 19, 1590–1596.CrossRefPubMedGoogle Scholar
  19. 19.
    Talpaz, M., Silver, R. T., Druker, B. J., Goldman, J. M., Gambacorti-Passerini, C., Guilhot, F., Schiffer, C. A., Fischer, T., Deininger, M. W. N., Lennard, A. L., Hochhaus, A., Ottmann, O. G., Gratwohl, A., Baccarani, M., Stone, R., Tura, S., Mahon, F.-X., Fernandes-Reese, S., Gathmann, I., Capdeville, R., Kantarjian, H., and Sawyers, Ch. L. (2002) Blood, 99, 1928–1937.CrossRefPubMedGoogle Scholar
  20. 20.
    Stromskaya, T. P., Rybalkina, E. Yu., Turkina, A. G., Zabotina, T. N., Logacheva, N. P., Zakharova, E. S., Mechetner, E. B., Baryshnikov, A. Yu., Khoroshko, N. D., and Stavrovskaya, A. A. (2001) Terap. Arkh., No. 7, 20–25.Google Scholar
  21. 21.
    Homolya, L., Hollo, Z., Muller, M., Mechetner E., and Sarkadi, B. (1996) Br. J. Cancer, 73, 849–855.CrossRefPubMedGoogle Scholar
  22. 22.
    Park, S. W., Lomri, N., Simeoni, L. A., Fruehauf, J. P., and Mechetner, E. (2003) Cytometry, 53A, 67–78.CrossRefGoogle Scholar
  23. 23.
    Mechetner, E. B. (2003) Biol. Membr. (Moscow), 20, 213–224.Google Scholar
  24. 24.
    Neyfakh, A. A. (1988) Exp. Cell Res., 174, 168–176.CrossRefPubMedGoogle Scholar
  25. 25.
    Zaman, G. J., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., Pinedo, H. M., Scheper, R. J., Baas, F., Broxterman, H. J., and Borst, P. (1994) Proc. Natl. Acad. Sci. USA, 91, 8822–8826.CrossRefPubMedGoogle Scholar
  26. 26.
    Bunting, K. D. (2002) Stem Cells, 20, 11–20.CrossRefPubMedGoogle Scholar
  27. 27.
    Dean, M., Fojo, T., and Bates, S. (2005) Nat. Rev. Cancer, 5, 275–284.CrossRefPubMedGoogle Scholar
  28. 28.
    De Grouw, E. P., Raaijmakers, M. H., Boezeman, J. B., van der Reijden, B. A., van de Locht, L. T., de Witte, T. J., Jansen, J. H., and Raymakers, R. A. (2006) Leukemia, 20, 750–754.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2008

Authors and Affiliations

  • T. P. Stromskaya
    • 1
    Email author
  • E. Yu. Rybalkina
    • 1
  • S. S. Kruglov
    • 2
  • T. N. Zabotina
    • 1
  • E. B. Mechetner
    • 3
  • A. G. Turkina
    • 2
  • A. A. Stavrovskaya
    • 1
  1. 1.Institute of Carcinogenesis, Blokhin Russian Cancer Research CenterRussian Academy of Medical SciencesMoscowRussia
  2. 2.National Hematology Research CenterRussian Academy of Medical SciencesMoscowRussia
  3. 3.University of California at IrvineIrvineUSA

Personalised recommendations