Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo.
About 97% of synovial sarcomas harbor the SYT-SSX fusion gene by chromosomal translocation. We found that the histone deacetylase (HDAC) inhibitor FK228 significantly suppressed the growth of synovial sarcoma cells as compared with that of osteosarcoma. The 50% growth inhibition IC50 value we obtained for FK228 was 0.02-0.2 nM, and it indicates that its suppression effect on synovial sarcoma cells is the highest of any of the HDAC inhibitors yet reported. It was not likely that the growth suppression of FK228 depends on the doubling time of these cells. Introduction of SYT-SSX cDNA into HEK293 cells enhanced the sensitivity of the cells for FK228. Immunostaining of the FK228-treated cells using an anti-acetyl-histone H3 antibody showed that FK228 inhibits deacetylation of histone. In a mice assay, the growth of synovial sarcoma cells was markedly inhibited by FK228 treatment, and the invasion of tumors into surrounding tissues was suppressed. These results suggest that FK228 may be useful in developing therapeutic strategies to treat synovial sarcoma.
Ito
Tatsuo
T
Science of Functional Recovery and Reconstruction, Graduate School of Medicine and Dentistry, Okayama University, Shikata-cho 2-5-1, Okayama 700-8558, Japan.
Ouchida
Mamoru
M
Morimoto
Yuki
Y
Yoshida
Aki
A
Jitsumori
Yoshimi
Y
Ozaki
Toshifumi
T
Sonobe
Hiroshi
H
Inoue
Hajime
H
Shimizu
Kenji
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D049109:Cell Proliferation; D047630:Depsipeptides / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013584:Sarcoma, Synovial / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin