FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells.
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.
Imai
Tsuyoshi
T
Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Adachi
Souichi
S
Nishijo
Koichi
K
Ohgushi
Masatoshi
M
Okada
Masayuki
M
Yasumi
Takahiro
T
Watanabe
Ken-ichiro
K
Nishikomori
Ryuta
R
Nakayama
Tomitaka
T
Yonehara
Shin
S
Toguchida
Junya
J
Nakahata
Tatsutoshi
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006657:Histones; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D019014:fas Receptor; C087123:romidepsin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases