Inhibition of proteasome by bortezomib increase chemosensitivity of bcr/abl positive human k562 chronic myleoid leukemia cells to imatinib

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.