論文 - 詳細
| RRC ID | 1343 |
|---|---|
| 著者 | Kawano T, Horiguchi-Yamada J, Iwase S, Akiyama M, Furukawa Y, Kan Y, Yamada H. |
| タイトル | 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. |
| ジャーナル | Anticancer Res |
| 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 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. |
| 巻・号 | 24(5A) |
| ページ | 2705-12 |
| 公開日 | 2004-1-1 |
| PMID | 15517875 |
| MeSH | Acetylation Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis / drug effects* Apoptosis / physiology Benzamides Cyclin D1 / biosynthesis* Cyclin D1 / genetics Depsipeptides / administration & dosage Depsipeptides / pharmacology* Dose-Response Relationship, Drug Drug Synergism Fusion Proteins, bcr-abl / biosynthesis* Histones / metabolism Humans Hydroxamic Acids / administration & dosage Hydroxamic Acids / pharmacology Imatinib Mesylate Immunoblotting K562 Cells MAP Kinase Kinase Kinases / biosynthesis* MAP Kinase Kinase Kinases / genetics MAP Kinase Signaling System / drug effects Piperazines / administration & dosage Piperazines / pharmacology* Proto-Oncogene Proteins c-myc / biosynthesis* Proto-Oncogene Proteins c-myc / genetics Pyrimidines / administration & dosage Pyrimidines / pharmacology* |
| IF | 1.994 |
| 引用数 | 20 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | K562(RCB0027) |