Depsipeptide Enhances Imatinib Mesylate-induced Apoptosis of Bcr-Abl-positive Cells and Ectopic Expression of Cyclin D1, c-Myc or Active MEK Abrogates this Effect

Abstract

Background: Imatinib mesylate (STI571) is the first-line drug for chronic myeloid leukemia (CML), but development of resistance to this drug is a clinical problem. To explore the effective use of STI571, we studied the combination treatment with histone deacetylase inhibitor (depsipeptide, FK228). Materials and Methods: FK228 and trichostatin A (TSA) were studied with respect to apoptosis of two Bcr-Abl-positive cell lines, K562 and TCC-S. Genetically-modified K562 cells by any of cyclin D1, c-Myc and active MEK genes were also studied. Apoptosis was examined by nuclear-morphology under a fluorescent microscope and by the expression of annexin V. Changes of apoptosis-regulating genes and acetylated histone H4 were studied by immunoblot. Results: FK228 showed cytotoxicity at the nano-molar level. Combination treatment with STI571 and FK228 enhanced the induction of apoptosis significantly compared with each single treatment, although the histone acetylation level was not changed by the co-treatment. The combination treatment activated caspase-3 and cleaved PARP, but it did not induce any notable change in the expression of Bcl-X_L, Bcl-2 and Bax compared with each single treatment. Enhanced apoptosis by the co-treatment was abrogated by ectopic expression of cyclin D1, c-Myc or active MEK. Conclusion: The combination of FK228 with STI571 is a promising treatment for Bcr-Abl-positive CML, but the activation of the MEK/ERK pathway and its downstream target genes may bring resistance to the co-treatment in leukemic cells.