Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells
Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells
复制标题
DOI：
10.1158/1078-0432.ccr-03-0100
复制
发表时间：
2004-02-01
影响因子：
11.5
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Takai, N;Desmond, JC;Koeffler, HP
目的：HDAC抑制剂（HDACIs）已被证明可以抑制癌细胞增殖，刺激细胞凋亡，并诱导细胞周期阻滞。我们的目的是探讨HDACIs [辛二酰苯胺bishydroxamine，丙戊酸（VPA），阿司他丁A，丁酸钠]对6个子宫内膜癌细胞株的抗增殖作用。实验设计：子宫内膜癌细胞进行了治疗与各种HDACIs，细胞生长，细胞周期和凋亡的影响进行了测量。VPA抑制免疫缺陷小鼠子宫内膜肿瘤生长的能力也assessed.Results：克隆形成试验表明，所有的癌细胞系敏感HDACIs的生长抑制作用。细胞周期分析表明HDACIs处理后S期细胞比例减少，G（0）-G（1）和/或G（2）-M期细胞比例增加。末端脱氧核苷酸转移酶介导的缺口末端标记法表明，HDACIs诱导细胞凋亡。这与恶性表型相关基因的表达改变相伴随，包括p21（Waf 1）、p27（KiP 7）和E-钙粘蛋白的增加以及Bcl-2和细胞周期蛋白-D1和-D2的减少。染色质免疫沉淀分析显示辛二酰苯胺双羟胺处理后，与p21启动子相关的乙酰化组蛋白水平显着增加。结论：HDACIs在体外和裸鼠体内均能有效抑制子宫内膜癌细胞的生长，且无毒副作用。这些发现提高了HDACIs可能被证明在治疗子宫内膜癌方面特别有效的可能性。
Purpose: HDAC inhibitors (HDACIs) have been shown to inhibit cancer cell proliferation, stimulate apoptosis, and induce cell cycle arrest. Our purpose was to investigate the antiproliferative effects of the HDACIs [suberoyl anilide bishydroxamine, valproic acid (VPA), trichostatin A, and sodium butyrate] against six endometrial cancer cell lines.Experimental Design: Endometrial cancer cells were treated with a variety of HDACIs, and the effect on cell growth, cell cycle, and apoptosis was measured. The ability of VPA to inhibit the growth of endometrial tumors growing in immunodeficient mice was also assessed.Results: Clonogenic assays showed that all cancer cell lines were sensitive to the growth inhibitory effect of HDACIs. Cell cycle analysis indicated that treatment with HDACIs decreased the proportion of cells in S phase and increased the proportion of cells in the G(0)-G(1) and/or G(2)-M phases of the cell cycle. Terminal deoxynucleotidyl transferase-mediated nick end labeling assays showed that HDACIs induced apoptosis. This was concomitant with altered expression of genes related to malignant phenotype, including an increase in p21(Waf1), p27 (KiP7), and E-cadherin and a decrease in Bcl-2 and cyclin-D1 and -D2. Chromatin immunoprecipitation analysis revealed a remarkable increase in levels of acetylated histones associated with the p21 promoter after suberoyl anilide bishydroxamine treatment. In nude mice experiments, VPA inhibited significantly human uterine tumor growth without toxic side effects.Conclusions: These results suggest that HDACIs are effective in inhibiting growth of endometrial cancer cells in vitro and in nude mice, without toxic side effects. The findings raise the possibility that HDACIs may prove particularly effective in treatment of endometrial cancers.