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.
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).


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.
Kawano
Takeshi
T
Department of Molecular Genetics, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan.
Horiguchi-Yamada
Junko
J
Iwase
Satsuki
S
Akiyama
Masaharu
M
Furukawa
Yusuke
Y
Kan
Yasuhiko
Y
Yamada
Hisashi
H
D000107:Acetylation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D020014:K562 Cells; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*
D001549:Benzamides; D047630:Depsipeptides; D006657:Histones; D006877:Hydroxamic Acids; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D019938:Cyclin D1; C012589:trichostatin A; D000068877:Imatinib Mesylate; C087123:romidepsin; D016044:Fusion Proteins, bcr-abl; D020930:MAP Kinase Kinase Kinases