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 (Ph-1)-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 Ph-1-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 ST1571. 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-Ph-1-leukemia effect of the combination of BCR/ABL kinase inhibitor ST1571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that ST1571 + WT exerted a synergistic effect against the Ph-1-positive cell lines, but did not affect the growth of Ph-1-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 ST1571 + WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to ST1571 and WT alone. In conclusion, combination of ST1571 + WT or ST1571 + LY may represent a novel approach against the Ph-1-positive leukemias.