Effect of the Combination of Imatinib Mesylate (Glivec) and Curcumin in Chronicm Myeloid Leukemia Cell Line.

Imatinib mesylate (Glivec, Gleevec, STI571) is highly effective in patients with chronic myeloid leukemia (CML). Despite high rates of hematologic and cytogenetic responses to Glivec therapy, the emergence of resistance to Glivec has been recognized as a major problem in the treatment of CML. Those problems leaded us to search for novel therapy, combining curcumin with Glivec. Recently we reported that curcumin induced apoptosis via repression of p-AKT and activation of caspase-3. To investigate whether combination of curcumin with Glivec is more effective than Glivec alone, the expression of apoptosis related genes, such as Bcl-2 family, caspase-3, and its cell cycle proteins, such as p53, p21, cyclin D, cyclin A, cyclin B1 and PCNA were examined by western analysis in K562 chronic myeloid leukemia cell line. Our results showed that Bcl-2, -XL, and Bid were more down-regulated with combined treatment compared with single treatment controls (either Glivec or curcumin alone). Also, the activity of caspase 3 was 2-fold higher than compared with control groups. In western analysis, procaspase 3 was dramatically reduced with combined treatment. Also, cell cycle proteins except p53 were more down-regulated in combined treatment. For further investigation of the genes affected by combination therapy, DNA chip analysis was performed. The expression of candidate genes, which we selected in chip analysis, was confirmed using real-time PCR. Our result indicated that apoptosis related genes were up-regulated and cyclin D1 and cyclin A were down-regulated. Also, several genes (protein phosphatase 2C, ZNF272, protein-tyrosine phosphatase nonreceptor 7 (PTPN7), SOCS2) were more down-regulated in combined treatment, showing 2-fold difference. Those genes may be associated with the progression of chronic myeloid leukemia. We suggest that their down-regulation by combined treatment was effective mainly via the induction of apoptosis. Taken together, our data suggested that combined treatment with curcumin could be effective to overcome the problems of Imatinib mesylate (Glivec, STI571) therapy.