Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo
Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo
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DOI：
10.1016/j.canlet.2004.10.030
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发表时间：
2005-06-28
期刊：
影响因子：
9.7
通讯作者：
Shimizu, K
中科院分区：
文献类型：
--
作者：
Ito, T;Ouchida, M;Shimizu, K
约97%的滑膜肉瘤通过染色体易位携带SYT-SSX融合基因。我们发现，组蛋白去乙酰化酶（HDAC）抑制剂FK 228显着抑制滑膜肉瘤细胞的生长相比，骨肉瘤。我们获得的FK 228的50%生长抑制IC 50值为0.02-0.2 nM，这表明其对滑膜肉瘤细胞的抑制作用是迄今报道的任何HDAC抑制剂中最高的。FK 228的生长抑制不太可能取决于这些细胞的倍增时间。将SYT-SSX cDNA导入HEK 293细胞中增强了细胞对FK 228的敏感性。使用抗乙酰组蛋白H3抗体对FK 228处理的细胞进行免疫染色，结果显示FK 228抑制组蛋白的脱乙酰化。在小鼠试验中，FK 228处理显着抑制了滑膜肉瘤细胞的生长，并抑制了肿瘤对周围组织的侵袭。这些结果表明，FK 228可能是有用的，在开发治疗策略，以治疗滑膜肉瘤。(c)2004爱思唯尔爱尔兰有限公司保留所有权利。
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-hi stone 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. (c) 2004 Elsevier Ireland Ltd. All rights reserved.