STI571 (imatinib; Gleevec®) developed as the molecularly targeted therapy is a potent and selective inhibitor of Bcr-Abl and is a first-line drug for the treatment of newly diagnosed CML patients. Although highly active in early stages of CML, STI571 seems unable to eradicate the malignant progenitors and several patients develop drug resistance after long-time use. Combination of STI571 with doxorubicin (DOX) was investigated to determine optimal concentrations of both drugs which could enhance the pro-apoptotic activity of STI571 in apoptosis reluctant cell line K562, derived from blast crisis CML patient. Analysis of cell proliferation has shown that STI571 and DOX exerted synergistic or additive effects on K562 cells depending on the concentrations used in the study. Examination of cell cycle indicated that DOX induced G₂/M arrest whereas dependence on concentrations of STI571 was observed when DOX was combined with different concentrations of STI571. The antiproliferative activities were mainly due to the effect on cellular differentiation when STI571 in the range of 100-250 nM was combined with 40 nM DOX and apoptosis when STI571 used in combinations was in the range of 250-800 nM. Both processes were accompanied by Δψ_m dissipation.

A low concentration of STI571 in combination with low concentration of DOX might be an alternative approach to high concentration of STI571 currently used in clinics. This therapeutic strategy might decrease the probability of STI571 resistance development and side effects caused by higher doses of DOX, and therefore increase the efficacy of chemotherapy against CML.

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