RRC ID 42043
著者 Imai T, Adachi S, Nishijo K, Ohgushi M, Okada M, Yasumi T, Watanabe K, Nishikomori R, Nakayama T, Yonehara S, Toguchida J, Nakahata T.
タイトル FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells.
ジャーナル Oncogene
Abstract We investigated the antitumor effects of FR901228, a HDAC inhibitor, on human osteosarcoma cells, in vitro and in vivo to explore its possible utility in the treatment of pediatric bone cancers. FR901228 caused marked growth inhibition with a 50% inhibitory concentration of 1.2-7.3 nM and induction of apoptosis in all eight osteosarcoma cell lines tested. These effects of FR901228 were also observed in vivo xenograft models on BALB/c nude mice, and treatment with 5.6 mg/kg/day resulting in a >70% reduction in the mean final tumor volume compared with the mean initial tumor volume. TUNEL assays demonstrated extensive apoptosis in tumor sections of mice treated with FR901228. Induction of apoptosis was preceded by increased expression of Fas ligand (FasL) mRNA, resulting in expression of membrane-bound FasL, which was followed by sequential activation of caspase-8 and -3. The level of apoptosis induction was reduced using a neutralizing anti-FasL antibody and overexpression of either the dominant-negative FADD or the viral FLICE inhibitory protein. Furthermore, treatment with a suboptimal dose of FR901228 greatly sensitized osteosarcoma cells to agonistic anti-Fas antibody-mediated apoptosis. These findings suggest that FR901228 is a highly promising antitumor agent against osteosarcoma, inducing apoptosis by the activation of the Fas/FasL system.
巻・号 22(58)
ページ 9231-42
公開日 2003-12-18
DOI 10.1038/sj.onc.1207184
PII 1207184
PMID 14647441
MeSH Animals Antibiotics, Antineoplastic / pharmacology* Apoptosis Blotting, Western Caspase 3 Caspase 8 Caspase 9 Caspases / metabolism Cell Division Cell Line, Tumor Cell Survival Depsipeptides* Dose-Response Relationship, Drug Fas Ligand Protein Flow Cytometry Histones / metabolism Humans In Situ Nick-End Labeling Inhibitory Concentration 50 Membrane Glycoproteins / metabolism* Mice Mice, Inbred BALB C Mice, Nude Neoplasm Transplantation Neoplasms / drug therapy* Osteosarcoma / drug therapy* Peptides, Cyclic / pharmacology* RNA, Messenger / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Time Factors Transfection fas Receptor / metabolism*
IF 7.971
引用数 59
WOS 分野 GENETICS & HEREDITY ONCOLOGY BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞 OST(RCB0454)