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

• Published in: Anticancer research 2004-09, Vol.24 (5A), p.2705-2712
• Main Authors: KAWANO, Takeshi, HORIGUCHI-YAMADA, Junko, IWASE, Satsuki, AKIYAMA, Masaharu, FURUKAWA, Yusuke, KANO, Yasuhiko, YAMADA, Hisashi
• Format: Article
• Language: English
• Subjects: Acetylation; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Benzamides; Biological and medical sciences; Chromosome aberrations; 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; Medical genetics; Medical sciences; Piperazines - administration & dosage; Piperazines - pharmacology; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - genetics; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Tumors
• ISSN: 0250-7005; 1791-7530

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.