Interactions between the kinase inhibitor STI571 and pharmacological antagonists of the @entity8047 ( @entity8047 )/mitogen-activated protein kinase (MAPK) cascade have been examined in @entity1 @entity2800 cells (K562 and LAMA 84) that express the @entity1861 kinase. Exposure of K562 cells to concentrations of STI571 that minimally induced apoptosis (e.g., approximately 200 nM) resulted in early suppression (i.e., at 6 h) of @entity22600 /44 MAPK phosphorylation followed at later intervals (i.e., > or =24 h) by a marked increase in @entity22600 /44 MAPK phosphorylation/activation. Coadministration of a nontoxic concentration of the @entity16629 inhibitor PD184352 (5 microM) prevented STI571-mediated activation of @entity22600 /44 MAPK. Cells exposed to STI571 in combination with PD184352 for 48 h demonstrated a very dramatic increase in mitochondrial dysfunction (e.g., loss of DeltaPsim and cytosolic @entity4674 release) associated with @entity522 activation, @entity12982 cleavage, and the appearance of the characteristic morphological features of apoptosis. Similar results were obtained using other pharmacological @entity16629 inhibitors (e.g., PD 98059 and U0126) as well as another leukemic cell line that expresses @entity1861 (e.g., LAMA 84). However, synergistic induction of apoptosis by STI571 and PD184352 was not observed in @entity1 @entity2800 cells that do not express the @entity1861 kinase (e.g., HL-60 and U937) nor in normal @entity1 peripheral blood mononuclear cells. Synergistic potentiation of STI571-mediated lethality by PD184352 was associated with multiple perturbations in signaling and apoptotic regulatory pathways, including caspase-dependent down-regulation of @entity1861 and @entity588 ; caspase-independent down-regulation of @entity1836 and @entity2423 ; activation of JNK, p38 MAPK, and @entity69573 ( @entity10610 ); and diminished phosphorylation of @entity11715 and @entity10366 . Significantly, coexposure to PD184352 strikingly increased the lethality of a pharmacologically achievable concentration of STI571 (i.e., 1-2 microM) in resistant K562 cells expressing marked increases in @entity1861 protein levels. Together, these findings raise the possibility that treatment of @entity1861 -expressing cells with STI571 elicits a cytoprotective MAPK activation response and that interruption of the latter pathway (e.g., by pharmacological @entity16629 inhibitors) is associated with a highly synergistic induction of @entity2383 and apoptosis. They also indicate that in the case of @entity1861 -positive cells, simultaneous interruption of two signal transduction pathways may represent an effective antileukemic strategy.

Pharmacologic @entity8047 /mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing XXXX leukemia cells.

@entity1 :: ('9606', 'Species') :: ['human'] @entity69573 :: ('55379', 'Gene') :: ['p34'] @entity1861 :: ('25', 'Gene') :: ['Bcr-Abl'] @entity10610 :: ('983', 'Gene') :: ['cdc2'] @entity8047 :: ('5609', 'Gene') :: ['mitogen-activated protein/extracellular signal-regulated kinase kinase', 'MEK'] @entity522 :: ('836', 'Gene') :: ['procaspase-3'] @entity588 :: ('596', 'Gene') :: ['Bcl-2'] @entity4674 :: ('54205', 'Gene') :: ['cytochrome c'] @entity1836 :: ('598', 'Gene') :: ['Bcl-x(L)'] @entity2423 :: ('4170', 'Gene') :: ['Mcl-1'] @entity2800 :: ('MESH:D007951', 'Disease') :: ['myeloid leukemia'] @entity12982 :: ('142', 'Gene') :: ['poly(ADP-ribose) polymerase'] @entity16629 :: ('5604;5605', 'Gene') :: ['MEK1/2'] @entity10366 :: ('1385', 'Gene') :: ['CREB'] @entity22600 :: ('8814', 'Gene') :: ['p42'] @entity11715 :: ('6776', 'Gene') :: ['Stat5'] @entity2383 :: ('MESH:D028361', 'Disease') :: ['mitochondrial damage']
@entity1 :: (9606,Species) :: ['human']
