College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
Food Chem Toxicol. 2011 Aug;49(8):1737-44. doi: 10.1016/j.fct.2011.04.019. Epub 2011 Apr 29.
This study is the first to investigate the antiproliferative effect of eupatilin in human endometrial cancer cells. Eupatilin, a naturally occurring flavonoid isolated from Artemisia princeps, has anti-inflammatory, anti-oxidative, and anti-tumor activities. In the present study, we investigated the potential effect of eupatilin on cell growth and its molecular mechanism of action in human endometrial cancer cells. Eupatilin was more potent than cisplatin in inhibiting cell viability in the human endometrial cancer cell lines Hec1A and KLE. Eupatilin showed relatively low cytotoxicity in normal human endometrial cells HES and HESC cells when compared to cisplatin. Eupatilin induced G2/M phase cell cycle arrest in a time- and dose-dependent manner, as indicated by flow cytometry analysis. In addition, treatment of Hec1A cells with eupatilin resulted in a significant increase in the expression of p21(WAF1/CIP1) and in the phosphorylation of Cdc25C and Cdc2. Knockdown of p21 using specific siRNAs significantly compromised eupatilin-induced cell growth inhibition. Interestingly, levels of mutant p53 in Hec1A cells decreased markedly upon treatment with eupatilin, and p53 siRNA significantly increased p21 expression. Moreover, eupatilin modulated the phosphorylation of protein kinases ERK1/2, Akt, ATM, and Chk2. These results suggest that eupatilin inhibits the growth of human endometrial cancer cells via G2/M phase cell cycle arrest through the up-regulation of p21 by the inhibition of mutant p53 and the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway.
这项研究首次探讨了芹菜素在人子宫内膜癌细胞中的增殖抑制作用。芹菜素是从青蒿中分离得到的一种天然黄酮类化合物,具有抗炎、抗氧化和抗肿瘤作用。在本研究中,我们研究了芹菜素对人子宫内膜癌细胞生长的潜在影响及其作用机制。与顺铂相比,芹菜素在人子宫内膜癌细胞系 Hec1A 和 KLE 中更能有效抑制细胞活力。与顺铂相比,芹菜素对正常人类子宫内膜细胞 HES 和 HESC 细胞的细胞毒性相对较低。流式细胞术分析表明,芹菜素呈时间和剂量依赖性诱导 G2/M 期细胞周期阻滞。此外,用芹菜素处理 Hec1A 细胞导致 p21(WAF1/CIP1)的表达和 Cdc25C 和 Cdc2 的磷酸化显著增加。用特异性 siRNAs 敲低 p21 显著削弱了芹菜素诱导的细胞生长抑制。有趣的是,在 Hec1A 细胞中,芹菜素处理后突变型 p53 的水平明显降低,而 p53 siRNA 显著增加了 p21 的表达。此外,芹菜素调节 ERK1/2、Akt、ATM 和 Chk2 蛋白激酶的磷酸化。这些结果表明,芹菜素通过抑制突变型 p53和激活 ATM/Chk2/Cdc25C/Cdc2 检查点途径而上调 p21,从而抑制人子宫内膜癌细胞的生长。