Interactions between the Bcr/Abl
kinase inhibitor
STI571 (
Gleevec,
imatinib mesylate) and
histone deacetylase inhibitors (HDIs) have been examined in STI571-sensitive and -resistant Bcr/Abl(+) human
leukemia cells (K562 and LAMA 84). Cotreatment of K562 cells with 250 nM
imatinib mesylate and 2.0 micro M
suberoylanilide hydroxamic acid (SAHA) for 24 h, exposures that were minimally toxic alone, resulted in a marked increase in mitochondrial damage (e.g.,
cytochrome c, Smac/DIABLO, and
apoptosis-inducing factor release),
caspase activation, and apoptosis. Similar events were observed in other Bcr/Abl(+) cells (i.e., LAMA 84), and in cells exposed to
STI571 in combination with the HDI
sodium butyrate. Coexposure of cells to HDIs in conjunction with
STI571 resulted in multiple perturbations in signaling and
cell cycle-regulatory proteins, including down-regulation of Raf, phospho-
mitogen-activated protein kinase kinase (
MEK), phospho-
extracellular signal-regulated kinase (ERK), phospho-Akt, phospho-signal transducers and activators of transcription 5,
cyclin D1, and Mcl-1, accompanied by dephosphorylation and cleavage of
retinoblastoma protein and a striking increase in phosphorylation of c-Jun NH(2)-terminal
kinase. Coexposure of Bcr/Abl(+) cells to
STI571 also blocked SAHA-mediated induction of p21(CIP1) and resulted in down-regulation of Bcr/Abl
protein expression.
STI571 and SAHA also interacted synergistically to induce apoptosis in STI571-resistant K562 and LAMA 84 cells that display increased Bcr/Abl
protein expression. Lastly, inducible expression of a constitutively active MEK1/2 construct significantly attenuated SAHA/
STI571-mediated apoptosis in K562 cells, implicating disruption of the Raf/
MEK/ERK axis in synergistic antileukemic effects of this
drug combination. Together, these findings indicate that combined exposure of Bcr/Abl(+) cells to the
kinase inhibitor
STI571 and HDIs leads to diverse perturbations in signaling and
cell cycle-regulatory proteins, associated with a marked increase in mitochondrial damage and cell death. They also raise the possibility that this strategy may be effective in some Bcr/Abl(+) cells that are resistant to
STI571 through increased Bcr/Abl expression.