米非司酮在体外和体内均能抑制卵巢癌细胞的生长。
Mifepristone inhibits ovarian cancer cell growth in vitro and in vivo.
作者信息
Goyeneche Alicia A, Carón Rubén W, Telleria Carlos M
机构信息
Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, South Dakota 57069, USA.
出版信息
Clin Cancer Res. 2007 Jun 1;13(11):3370-9. doi: 10.1158/1078-0432.CCR-07-0164.
PURPOSE
These studies were designed to determine whether the synthetic steroid mifepristone inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved.
EXPERIMENTAL DESIGN
The effect of mifepristone on ovarian cancer cell growth in vitro was studied in ovarian cancer cell lines of different genetic backgrounds (SK-OV-3, Caov-3, OV2008, and IGROV-1). In addition, the growth inhibition capacity of mifepristone on ovarian carcinoma xenografts was tested in nude mice.
RESULTS
Mifepristone inhibited ovarian cancer cell proliferation in a dose- and time-dependent manner. The cytostatic effect of mifepristone was confirmed in a clonogenic survival assay and was not linked to loss of viability. Mifepristone blocked DNA synthesis, arrested the cell cycle at the G(1)-S transition, up-regulated cyclin-dependent kinase (cdk) inhibitors p21(cip1)and p27(kip1), down-regulated transcription factor E2F1, decreased expression of the E2F1-regulated genes cdk1 (cdc2) and cyclin A, and modestly decreased cdk2 and cyclin E levels. The abrupt arrest in cell growth induced by mifepristone correlated with reduced cdk2 activity, increased association of cdk2 with p21(cip1) and p27(kip1), increased nuclear localization of the cdk inhibitors, and reduced nuclear abundance of cdk2 and cyclin E. In vivo, mifepristone significantly delayed the growth of ovarian carcinoma xenografts in a dose-dependent manner and without apparent toxic effects for the animals.
CONCLUSIONS
These preclinical studies show that mifepristone is effective as a single agent in vitro and in vivo, inhibiting the growth of human epithelial ovarian cancer cells. Mifepristone markedly reduces cdk2 activity likely due to increased association of cdk2 with the cdk inhibitors p21(cip1) and p27(kip1) and reduced nuclear cdk2/cyclin E complex availability. Acting as a cytostatic agent, mifepristone promises to be of translational significance in ovarian cancer therapeutics.
目的
这些研究旨在确定合成类固醇米非司酮是否在体外和体内抑制卵巢癌生长以及涉及的分子机制。
实验设计
在具有不同遗传背景的卵巢癌细胞系（SK-OV-3、Caov-3、OV2008和IGROV-1）中研究米非司酮对卵巢癌细胞体外生长的影响。此外，在裸鼠中测试米非司酮对卵巢癌异种移植物的生长抑制能力。
结果
米非司酮以剂量和时间依赖性方式抑制卵巢癌细胞增殖。米非司酮的细胞生长抑制作用在克隆形成存活试验中得到证实，且与活力丧失无关。米非司酮阻断DNA合成，使细胞周期停滞在G(1)-S期转换，上调细胞周期蛋白依赖性激酶（cdk）抑制剂p21(cip1)和p27(kip1)，下调转录因子E2F1，降低E2F1调节基因cdk1（cdc2）和细胞周期蛋白A的表达，并适度降低cdk2和细胞周期蛋白E水平。米非司酮诱导的细胞生长突然停滞与cdk2活性降低、cdk2与p21(cip1)和p27(kip1)的结合增加、cdk抑制剂的核定位增加以及cdk2和细胞周期蛋白E的核丰度降低相关。在体内，米非司酮以剂量依赖性方式显著延迟卵巢癌异种移植物的生长，且对动物无明显毒性作用。
结论
这些临床前研究表明，米非司酮作为单一药物在体外和体内均有效，可抑制人上皮性卵巢癌细胞的生长。米非司酮显著降低cdk2活性，可能是由于cdk2与cdk抑制剂p21(cip1)和p27(kip1)的结合增加以及核cdk2/细胞周期蛋白E复合物可用性降低。作为一种细胞生长抑制剂，米非司酮有望在卵巢癌治疗中具有转化意义。
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