Human ovarian carcinoma cells: Histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis
Human ovarian carcinoma cells: Histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis
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DOI：
10.1002/cncr.20709
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发表时间：
2004-12-15
期刊：
影响因子：
6.2
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Takai, N;Kawamata, N;Koeffler, HP
背景组蛋白去乙酰化酶抑制剂（HDACls）可以抑制恶性肿瘤细胞的增殖，刺激细胞凋亡，并诱导细胞周期阻滞。作者研究了四种HDACIs在体外和体内对九种卵巢癌细胞系的影响。卵巢癌细胞用各种HDACIs处理，并研究它们对细胞生长、细胞周期、凋亡和相关事件的影响。还评估了丙戊酸（VPA）抑制免疫缺陷小鼠卵巢肿瘤生长的能力。克隆形成试验表明，所有的卵巢癌细胞系敏感的HDACIs的生长抑制作用。细胞周期分析表明，HDACIs使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尿苷三磷酸末端标记试验表明，HDACIs诱导细胞凋亡，这与细胞凋亡，细胞生长和恶性表型相关的基因表达的改变，包括caspase-9和caspase-3的激活一致。染色质免疫沉淀分析显示，辛二酰苯胺双羟沙明处理后，与p21启动子相关的乙酰化组蛋白水平显着增加。此外，在裸鼠实验中，VPA显著抑制人卵巢肿瘤生长，且无毒副作用。目前的研究结果表明，HDACIs可能在治疗卵巢肿瘤方面特别有效。(C)2004年美国癌症协会。
BACKGROUND. Histone deacetylase inhibitors (HDACls) can inhibit proliferation, stimulate apoptosis, and induce cell cycle arrest in malignant cells.METHODS. The authors investigated the effects of four HDACIs on nine ovarian carcinoma cell lines in vitro and in vivo. Ovarian carcinoma cells were treated with a variety of HDACIs, and their effects on cell growth, the cell cycle, apoptosis, and related events were investigated. The ability of valproic acid (VPA) to inhibit the growth of ovarian tumors in immunodeficient mice was also assessed.RESULTS. Clonogenic assays showed that all ovarian carcinoma cell lines were sensitive to the growth-inhibitory effects of the HDACIs. Cell cycle analysis indicated that their exposure to 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 deoxynucleotidyltransferase-mediated uridine triphosphate end-labeling assays demonstrated that HDACIs induced apoptosis, which occurred in concert with alterations in the expression of genes related to apoptosis, cell growth, and malignant phenotype, including the activation of caspase-9 and caspase-3. Chromatin immunoprecipitation analysis revealed a notable increase in levels of acetylated histones associated with the p21 promoter after treatment with suberoylanilide bishvdroxamine. In addition, in experiments involving nude mice, VPA significantly inhibited human ovarian tumor growth without toxic side effects.CONCLUSIONS. The results of the current study suggest that HDACIs may be particularly effective in the treatment of ovarian tumors. (C) 2004 American Cancer Society.