J Appl Biomed 4:95-104, 2006 | DOI: 10.32725/jab.2006.009

Imatinib mesylate affects tyrosine kinase activity in both leukemic and normal primary mononuclear blood cells

Kateřina Kuželová*, Dana Grebeňová, Michaela Pluskalová, Iuri Marinov, Hana Klamová, Zbyněk Hrkal
Institute of Haematology and Blood Transfusion, U Nemocnice 1, 128 20 Praha 2, Czech Republic

Tyrosine kinase (TK) activity in primary mononuclear blood cells (MNBC) derived from chronic myelogenous leukemia (CML) patients in the chronic phase as well as from healthy donors was measured by a sensitive time-resolved fluorescence method using the Delfia® Tyrosine Kinase kit. The level of phosphotyrosine was assessed in parallel by flow-cytometry. The experimental protocol for Delfia® was optimized using a K562 cell line. A large part (20 to 50%) of the fluorescence signal from K562 cells was sensitive to Imatinib mesylate, an inhibitor of Bcr-Abl tyrosine kinase, which is currently the leading drug in CML treatment. In primary MNBC, the direct contribution of Bcr-Abl itself to the signal was low. However, a 48h treatment of MNBC with 5 μM Imatinib resulted in a significant reduction of the observed TK activity (mean TK activity value: 56% of control) paralleled by a decrease in the phosphotyrosine level in the CML group. Modification of TK activity by Imatinib was observed also in the donor group. Imatinib mesylate thus probably affects cell signalization even in Bcr-Abl negative cells.

Keywords: tyrosin-kinase activity; Imatinib; K562; primary blood cells; leukemia

Received: December 9, 2005; Revised: January 14, 2006; Published: July 31, 2006  Show citation

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Kuželová K, Grebeňová D, Pluskalová M, Marinov I, Klamová H, Hrkal Z. Imatinib mesylate affects tyrosine kinase activity in both leukemic and normal primary mononuclear blood cells. J Appl Biomed. 2006;4(2):95-104. doi: 10.32725/jab.2006.009.
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    References

    1. Appel S., Boehmler A.M., Grünebach F. et al.: Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 103:538-544, 2004. Go to original source... Go to PubMed...
    2. Bartolovic K., Balabanov S., Hartmann U. et al.: Inhibitory effect of imatinib on normal progenitor cells in vitro. Blood 103:523-529, 2004. Go to original source... Go to PubMed...
    3. Baskaynak G., Kreuzer K.A., Schwarz M. et al.: Squamous cutaneous epithelial cell carcinoma in two CML patients with progressive disease under imatinib treatment. Eur. J. Haematol. 70:231-4, 2003. Go to original source... Go to PubMed...
    4. Calabretta B., Perrotti D.: The biology of CML blast crisis. Blood 103:4010-4022, 2004. Go to original source... Go to PubMed...
    5. Cwynarski K., Laylor R., Macchiarulo E. et al.: Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 18:1332-1339, 2004. Go to original source... Go to PubMed...
    6. Deininger M.W.N., Goldman J.M., Lydon N., Melo J.V.: The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90:3691-3698, 1997. Go to original source...
    7. Deininger M., Buchdunger E., Druker B.J.: The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640-2653, 2005. Go to original source... Go to PubMed...
    8. Dewar A.L., Cambareri A.C., Zannettino A.C.W. et al.: Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 105:3127-3132, 2005. Go to original source... Go to PubMed...
    9. Dewar A.L., Domaschenz R.M., Doberty K.V. et al.: Imatinib inhibits the in vitro development of the monocyte/macrophage lineage from normal human bone marrow progenitors. Leukemia 17:1713-1721, 2003. Go to original source... Go to PubMed...
    10. Dong R., Cwynarski K., Entwistle A. et al.: Dendritic cells from CML patients have altered actin organization, reduced antigen processing and impaired migration. Blood 101:3560-3567, 2003. Go to original source... Go to PubMed...
    11. Druker B.J., Tamura S., Buchdunger E. et al.: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2: 561-566, 1996. Go to original source... Go to PubMed...
    12. Fang G., Kim C.N., Perkins C.L. et al.: CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. Blood 96:2246-2253, 2000. Go to original source...
    13. Ferrao P.T., Frost M.J., Siah S.P., Ashman L.K.: Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood 102:4499-4503, 2003. Go to original source... Go to PubMed...
    14. Gambacorti-Passerini C., Le Coutre P., Mologni L. et al.: Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol. Dis. 23:380-394, 1997. Go to original source... Go to PubMed...
    15. Grebeňová D., Kuželová K., Smetana K. et al.: Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells. J. Photochem. Photobiol. B, Biol. 69:71-85, 2003. Go to original source... Go to PubMed...
    16. Guo J.Q., Lian J.Y., Xian Y.M. et al.: BCR-ABL Protein expression in peripheral blood cells of chronic myelogenous leukemia patients undergoing therapy. Blood 83:3629-3637, 1994. Go to original source... Go to PubMed...
    17. Holtz M.S., Slovak M.L., Zhang F. et al.: Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99:3792-3800, 2002. Go to original source... Go to PubMed...
    18. Jacquel A., Herrant M., Legros L. et al.: Imatinib induces mitochondria-dependent apoptosis of the Bcr-Abl positive K562 cell line and its differentiation towards the erythroid lineage. FASEB J. 17:2160-2162, 2003. Go to original source... Go to PubMed...
    19. Kantarjian H., Talpaz M., O'Brien S. et al.: High-dose imatinib therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873-8, 2004. Go to original source... Go to PubMed...
    20. Kawano T., Horiguchi-Yamada J., Saito S. et al.: Ectopic cyclin D1 expression blocks STI571-induced erythroid differentiation of K562 cells. Leuk. Res. 28:623-629, 2004. Go to original source... Go to PubMed...
    21. Kotaki M., Motoji T., Takanashi M. et al.: Anti-proliferative effect of the abl tyrosine kinase inhibitor STI571 on the P-glycoprotein positive K562/ADM cell line. Cancer Lett. 199:61-68, 2003. Go to original source... Go to PubMed...
    22. Krystal G.W.: Imatinib mesylate (STI571) for myeloid malignancies other than CML. Leuk. Res. 28S1: S53-S59, 2004. Go to original source...
    23. Kuželová K., Grebeňová D., Marinov I., Hrkal Z.: Fast apoptosis and erythroid differentiation induced by Imatinib mesylate in JURL-MK1 cells. J. Cell. Biochem. 95:268-280, 2005. Go to original source... Go to PubMed...
    24. Le Coutre P., Kreuzer K.A., Pursche S. et al.: Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother. Pharmacol. 53:313-23, 2004. Go to original source... Go to PubMed...
    25. Mahon F.X., Deininger M.W.N., Schultheis B. 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 96:1070-1079, 2000. Go to original source...
    26. Mahon F.X., Belloc F., Lagarde V. et al.: MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101:2368-2373, 2003. Go to original source... Go to PubMed...
    27. Manley P.W., Cowan-Jacob S.W., Buchdunger E. et al.: Imatinib: a selective tyrosine kinase inhibitor. Eur. J. Cancer 38:S19-S27, 2002. Go to original source... Go to PubMed...
    28. Mattiuzzi G.N., Cortes J.E., Talpaz M. et al.: Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate. Clin. Cancer Res. 9:976-80, 2003.
    29. Mohty M., Jourdan E., Mami N.B. et al.: Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia. Blood 103:4666-4668, 2004. Go to original source... Go to PubMed...
    30. Mukai M., Che X.F., Furukawa T. et al.: Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells. Cancer Sci. 94: 557-563, 2003. Go to original source... Go to PubMed...
    31. Rodley P., McDonald M., Price B. et al.: Comparative genomic hybridization reveals previously undescribed amplifications and deletions in the chronic myeloid leukemia-derived K-562 cell line. Genes Chromosomes Cancer 19:36-42, 1997. Go to original source...
    32. Sawyers C.L., Hochhaus A., Feldman E. et al.: Imatinib induces hematological and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530-9, 2002. Go to original source... Go to PubMed...
    33. Shaul Y., Ben-Yehoyada M.: Role of c-Abl in the DNA damage stress response. Cell Res. 15:33-35, 2005. Go to original source... Go to PubMed...
    34. Steelman L.S., Pohnert S.C., Shelton J.G. et al.: JAK/STAT, RaF/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18:189-218, 2004. Go to original source... Go to PubMed...
    35. Taieb J., Maruyama K., Borg C. et al.: Imatinib mesylate impairs Flt3L-mediated dendritic cell expansion and antitumor effects in vivo. Blood 103:1966-1967, 2004. Go to original source...
    36. Takahashi N., Miura I., Saitoh K., Miura A.B.: Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 92:4758-4763, 1998. Go to original source...
    37. Talpaz M., Silver R.T., Druker B.J. et al.: Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928-37, 2002. Go to original source... Go to PubMed...
    38. Traina F., Carvalheira J.B.C., Saad M.J.A. et al.: BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells. FEBS Lett. 535:17-22, 2003. Go to original source... Go to PubMed...
    39. Weisberg E., Griffin J.D.: Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 95:3498-3505, 2000. Go to original source...
    40. Wu S.Q., Voelkerding K.V., Sabatini L. et al.: Extensive amplification of bcr/abl fusion genes clustered on three marker chromosomes in human leukemic cell line K-562. Leukemia 9: 858-862, 1995.

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