RRC ID |
42043
|
Author |
Imai T, Adachi S, Nishijo K, Ohgushi M, Okada M, Yasumi T, Watanabe K, Nishikomori R, Nakayama T, Yonehara S, Toguchida J, Nakahata T.
|
Title |
FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells.
|
Journal |
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.
|
Volume |
22(58)
|
Pages |
9231-42
|
Published |
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
|
Times Cited |
59
|
WOS Category
|
GENETICS & HEREDITY
ONCOLOGY
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
Resource |
Human and Animal Cells |
OST(RCB0454) |