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Histone Deacetylase Inhibitors Promote STI571-mediated Apoptosis in STI571-sensitive and -resistant Bcr/Abl⁺ Human Myeloid Leukemia Cells¹

Departments of Medicine [C. Y., M. R., J. A., G. K., S. G.], Microbiology [G. K., D. C., S. G.], Human Genetics [M. S.], Pharmacology [S. G.], and Radiation Oncology [P. D.], Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298, and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts [L. V.]

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 µM 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 NH₂-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.

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