ABSTRACT Chronic myeloid leukaemia (CML) results from a translocation between chromosomes 9 and 22 which generates the BCR/ABL fusion oncopro-tein. BCR/ABL has constitutively tyrosine kinase activity resulting in leukemogenesis. Imatinib, a competitive inhibitor of the BCR/ABL tyrosine kinase, is the common treatment of CML. Despite the outstanding results of imatinib in the chronic phase of CML, cases of treatment failure have been reported, resulting in hetero-geneous molecular response. Bortezomib is a reversible inhibitor of the 26S proteasome in-ducing cell cycle arrest in G2/M phase, apop-tosis by inhibition of NF-kB. In this study, we examined the possible synergistic apoptotic effects of the imatinib/bortezomib combination and the responsible apoptotic mechanisms in-duced by this combination in K562 cells. The results of this study showed increased cyto-toxicity by XTT assay in combination of imatinib and bortezomib as compared to any agent alone. On the other hand, synergistic apoptotic affects of combination of these agents were also con-firmed by changes in caspase-3 enzyme activity and mitochondrial membrane potential. Taking together, all the results, confirming each other, showed that the combination of the imatinib and bortezomib has considerable synergistic effects on the apoptosis through increase in caspase-3 enzyme activity and decrease in mitochondrial membrane potential in human K562 CML cells.
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nullYusuf, B. , Oztekin, C. and Yonca, B. (2009) Inhibition of proteasome by bortezomib increase chemosensitivity of bcr/abl positive human k562 chronic myleoid leukemia cells to imatinib. Health, 1, 320-324. doi: 10.4236/health.2009.14052.
 Kuroda, J., Kimura, S., Andreeff, M., et al (2007) ABT-737 is a useful component of combinatory chemo-therapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. British Journal of Haema-tology, 140, 181-190.
Deininger, M., Buchdunger, E., Druker, B.J., et al (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood, 105, 2640-53.
Dulucq, S., Bouchet, S., Turcq, B., et al (2008) Mul-tidrug resistance gene (MDR1) polymorphisms are asso-ciated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood, 112, 2024-2027.
Kikuchi, S., Nagai, T., Kunitam, M., et al (2007) Active FKHRL1 overcomes imatinib resistance in chronic mye-logenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci, 98(12),1949-58.
Heaney, N.B., Holyoake, T.L. (2007) Therapeutic targets in chronic myeloid leukaemia. Hematol. Oncol, 25, 66-75.
Baran, Y., Salas, A., Senkal, C., et al (2007) Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apop-tosis in K562 human chronic myeloid leukemia cells. The J of Biol Chem, 282(15), 10922-10934.
Baran, Y., Ural, A.U., Gunduz, U. (2007) Mechanisms of cellular resistance to imatinib in human chronic myeloid leukemia cells. Hematology, 12, 497-503.
Fausel, C. (2007) Targeted chronic myeloid leukemia therapy: Seeking a cure. J. of Managed Care Pharmacy, 13(8), 8-12.
Talpaz, M., Shah, N.P., Kantarjian, H., et al (2006) Dasatinib in imatinib-resistant Philadelphia chromo-some–positive leukemias. N Engl J Med, 354, 2531-41.
Kuroda, J., Kimura, S., Strasser, A., et al (2007) Apop-tosis-based dual molecular targeting by INNO-406, a second-generation BCR/ABL inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against BCR/ABL-positive leukemia. Cell Death and Differen-tiation, 14, 1667-1677.
Quintas-Cardama, A., Cortes, J. (2008) Molecular biol-ogy of bcr-abl1-positive chronic myeloid leukemia. Blood, Doi:10.1182/blood-2008-03-144790.
Kwee, J.K., Luque, D.G., dos Santos Ferreira, A.C., et al (2008) Modulation of reactive oxygen species by anti-oxidants in chronic myeloid leukemia cells enhances imatinib sensitivity through survivin downregulation. Anti-Cancer Drugs, 19, 975–981.
Wiberg, K., Carlson, K., Aleskog, A., et al (2008) In vitro activity of bortezomib in cultures of patient tumour cells—potential utility in haematological malignancies. Med Oncol, Doi:10.1007/s12032-008-9107-6.
Fennell, D.A., Chacko, A., Mutti, L. (2008) BCL-2 fam-ily regulation by the 20S proteasome inhibitor borte-zomib. Oncogene, 27, 1189–1197.
Faderl, S., Rai, K., Gribben, J., et al (2006) Phase II study of single-agent bortezomib for the treatment of pa-tients with fludarabine-refractory B-cell chronic lym-phocytic leuk cancer. 107(5), 916-24.
Galimberti, S., Canestraro, M., Pacini, S., et al (2008) PS-341 (bortezomib) inhibits proliferation and induces apoptosis of megakaryoblastic MO7-e cells. Leuk Res, 32(1), 103-12.
Combaret, V., Boyault, S., Iacono, I., et al (2008) Effect of bortezomib on human neuroblastoma: analysis of mo-lecular mechanisms involved in cytotoxicity. Mol Cancer, Doi:10.1186/1476-4598-7-50.
McCloskey, S.M., McMullin, M.F., Walker, B., et al (2008) The therapeutic potential of the proteasome in leukaemia. Hematol Oncol, 26, 73-81.
Barr, P., Fisher, R., Friedberg J. (2007) The role of bor-tezomib in the treatment of lymphoma. Can Invest, 25, 766-775.
Armand, J.-P., Burnett, A.K., Drach, J., et al (2007) The emerging role of targeted therapy for hematologic ma-lignancies: Update on bortezomib and tipifarnib. The Oncologist, 12, 281-290.
Ludwig, H., Khayat, D., Giaccone, G., et al (2005) Pro-teasome inhibition and its clinical prospects in the treat-ment of hematologic and solid malignancies. Cancer, 104(9), 1794-1807.
Gore, S.D., Hermes-DeSantis, E.R. (2008) Future direc-tions in myelodysplastic syndrome: Newer agents and the role of combination approaches. Cancer Control, 15(4), 40-9.
Hind, D., Tappenden, P., Tumur, I., et al (2008) The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: Systematic review and economic evaluation. Health Technol Assess, 12(15), 1-182.
Shimizu, H., Tanaka, K., Ikeda, S., et al (2008) Util-ity-based evaluation of the quality of life of patient's with gastric cancer who receive chemotherapy--comparison of patients' quality of life between oral TS-1 and conven-tional injectable combination therapy. Yakugaku Zassh,i 28(5), 783-93.
Shen, L., Au, W.-Y., Guo, T., et al (2007) Proteasome inhibitor bortezomib-induced apoptosis in natural killer (NK)–cell leukemia and lymphoma: an in vitro and in vivo preclinical evaluation. Blood, 110, 469-470.
Yong, A.S.M., Keyvanfar, K., Hensel, N., et al. (2008) Primitive quiescent CD34+ cells in chronic myeloid leu-kemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood, Doi:10.1182/blood-2008-05-158253.
Yu, C., Friday, B.B., Lai, J.-P., et al (2006) Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther, 5(9),2378–87.
Yu, C., Rahmani, M., Conrad, D., et al (2003) The pro-teasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl cells sensitive and resistant to STI571. Blood, 102, 3765-3774.
Fruehauf, S., Topaly, J., Buss, E.C., et al (2007) Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer, 109(8), 1543-9.