Imatinib-resistant K562 cells are more sensitive to celecoxib, a selective COX-2 inhibitor: Role of COX-2 and MDR-1.

摘要

Selective inhibition of the BCR/ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is the therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses with imatinib, mainly due to the mutations in the Abl kinase domain, resistance occurs in patients with advanced disease. In the present study on imatinib-resistant K562 cells (IR-K562), however, no such mutations in the Abl kinase domain were observed. Further studies revealed the over-expression of COX-2 and MDR-1 in IR-K562 cells suggesting the possible involvement of COX-2 in the development of resistance to imatinib. So, we sought to examine the effect of celecoxib, a selective COX-2 inhibitor, on IR-K562 cells. The results clearly indicate that celecoxib is more effective in IR-K562 cells with a lower IC(50) value of 10muM compared to an IC(50) value of 40muM in K562 cells. This increase in the sensitivity of IR-K562 cells towards celecoxib suggests that the development ofresistance in IR-K562 cells is COX-2 dependent. Further studies revealed down-regulation of MDR-1 by celecoxib and a decline in p-Akt levels. Celecoxib-induced apoptosis of IR-K562 cells led to release of cytochrome c, PARP cleavage and decreased Bcl2/Bax ratio. Also, celecoxib at 1muM concentration induced apoptosis in IR-K562 cells synergistically with imatinib by reducing the IC(50) value of imatinib from 10 to 6muM. In conclusion, the present study indicates over-expression of COX-2 and MDR-1 in IR-K562 cells and celecoxib, a COX-2 specific inhibitor, induces apoptosis by inhibiting COX-2 and down-regulating MDR-1 expression through Akt/p-Akt signaling pathway.