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.
Anticancer Res
; 24(5A): 2705-12, 2004.
Article
en En
| MEDLINE
| ID: mdl-15517875
ABSTRACT
BACKGROUND:
Imatinib mesylate (ST1571) is the first-line drugfor chronic myeloid leukemia (CML), but development of resistance to this drug is a clinical problem. To explore the effective use of ST1571, we studied the combination treatment with histone deacetylase inhibitor (depsipeptide, FK228). MATERIALS ANDMETHODS:
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 MEKCONCLUSION:
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.
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Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Pirimidinas
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Protocolos de Quimioterapia Combinada Antineoplásica
/
Proteínas Proto-Oncogénicas c-myc
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Proteínas de Fusión bcr-abl
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Apoptosis
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Ciclina D1
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Quinasas Quinasa Quinasa PAM
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Depsipéptidos
Idioma:
En
Revista:
Anticancer Res
Año:
2004
Tipo del documento:
Article