RT Journal Article
SR Electronic
T1 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
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 2705
OP 2712
VO 24
IS 5A
A1 KAWANO, TAKESHI
A1 HORIGUCHI-YAMADA, JUNKO
A1 IWASE, SATSUKI
A1 AKIYAMA, MASAHARU
A1 FURUKAWA, YUSUKE
A1 KANO, YASUHIKO
A1 YAMADA, HISASHI
YR 2004
UL http://ar.iiarjournals.org/content/24/5A/2705.abstract
AB 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-XL, 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. Copyright© 2004 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved