Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571

BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph1-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. We decided to search for a more specific partner compound for STI571. Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells (Blood, 86:726,1995). Therefore the anti- Ph1-leukemia effect of the combination of BCR/ABL kinase inhibitor STI571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that STI571+WT exerted a synergistic effect against the Ph1-positive cell lines, but did not affect the growth of Ph1-negative cell line. Moreover, the combinations of STI571+WT or STI571+LY were effective in the inhibition of clonogenic growth of CML-chronic phase and CML-blast crisis patient cells, while sparing normal bone marrow cells. Single colony RT–PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph1-positive leukemias.