Abstract
The in vitro activity of STI571, an inhibitor of the Abl group of protein-tyrosine kinases, alone or in combination with camptothecin (CPT), a specific topoisomerase I inhibitor, was evaluated against human cancer cells with different metastatic capacity and drug resistance potency. These cell lines showed different sensitivity to STI571 on growth inhibition, and the expression of DNA-dependent protein kinase (DNA-PK), which interacts constitutively with c-Abl, was significantly decreased in drug sensitive CEM and MCF-7 cells and poorly metastatic PC3 and KM12 cells as compared with that of multidrug resistant CEM/MDR and MCF-7/MDR cells and highly metastatic PC3-MM2 and KM/L4a cells, respectively. These results suggest differential modulation of DNA-PK by STI571 treatment in drug resistance and metastatic degree dependent manner. We showed that CPT as well as STI571 significantly inhibits the expression of DNA-PK. The combined treatment with STI571 and CPT revealed synergistic effect, and the effect was accompanied by inhibition of cell proliferation due to significant reduced expression of DNA-PK components, which resulted in CPT sensitizes human cancer cells resistant to STI571. Therefore, the results of our study suggested that the suppression of DNA-PK using combination of STI571 and CPT could be a novel molecular target for against drug resistant and metastatic cancer cells.
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