Laboratory of Clinical Biology and Pharmacogenomics, Department of Cancer Preventive Material Development, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, South Korea.
Mol Cell Biochem. 2012 Apr;363(1-2):119-28. doi: 10.1007/s11010-011-1164-z. Epub 2011 Dec 7.
Costunolide (C(15)H(20)O(2)) is a sesquiterpene lactone that was isolated from many herbal medicines and it has diverse effects according to previous reports. However, the anti-cancer effects and the mechanism of actions are still unknown in breast cancer. In this study, we first observed that costunolide inhibits cell growth in a dose-and time-dependent manner. To examine the mechanism by which costunolide inhibits cell growth, we checked the effect of costunolide on apoptosis and the cell cycle. Costunolide induced apoptosis through the extrinsic pathway, including the activation of Fas, caspase-8, caspase-3, and degradation of PARP. However, did not have the same effect on the intrinsic pathway as revealed by analysis of mitochondrial membrane potential (Δψm) with JC-1 dye and expression of Bcl2 and Bax proteins level. Furthermore, costunolide induced cell cycle arrest in the G2/M phase via decrease in Cdc2, cyclin B1 and increase in p21WAF1 expression, independent of p53 pathway in p53-mutant MDA-MB-231 cells and increases Cdc2-p21WAF1 binding. In addition, costunolide had a slight induced effect on ROS generation. Among the mechanisms of p21WAF1 induction examined, costunolide-induced increase in p21WAF1 expression was related with protein stability and ROS generation. Through this study we confirm that costunolide induces G2/M cell cycle arrest and apoptotic cell death via extrinsic pathway in MDA-MB-231 cells suggesting that it could be a promising anticancer drug especially for ER-negative breast cancer.
标题：Costunolide 通过 Fas/FasL 途径诱导 MDA-MB-231 细胞凋亡和 G2/M 期阻滞
摘要：前言：Costunolide (C(15)H(20)O(2)) 是一种倍半萜内酯，已从多种草药中分离得到，根据以往的报道，它具有多种作用。然而，其在乳腺癌中的抗癌作用及其作用机制尚不清楚。本研究首先观察到 Costunolide 呈剂量和时间依赖性地抑制细胞生长。为了研究 Costunolide 抑制细胞生长的机制，我们检查了 Costunolide 对细胞凋亡和细胞周期的影响。Costunolide 通过 Fas/FasL 途径诱导细胞凋亡，包括 Fas 的激活、caspase-8、caspase-3 的活化和 PARP 的降解。然而，通过 JC-1 染料检测线粒体膜电位 (Δψm) 和 Bcl2 和 Bax 蛋白水平的表达，发现 Costunolide 对内在途径没有相同的作用。此外，Costunolide 通过降低 Cdc2、cyclin B1 和增加 p21WAF1 的表达诱导细胞周期 G2/M 期阻滞，而在 p53 突变型 MDA-MB-231 细胞中不依赖于 p53 途径，并增加 Cdc2-p21WAF1 结合。此外，Costunolide 对 ROS 的生成有轻微的诱导作用。在检查的 p21WAF1 诱导机制中，Costunolide 诱导的 p21WAF1 表达增加与蛋白稳定性和 ROS 生成有关。通过本研究我们证实 Costunolide 通过 Fas/FasL 途径诱导 MDA-MB-231 细胞发生 G2/M 期细胞周期阻滞和凋亡性细胞死亡，提示它可能是一种很有前途的抗癌药物，特别是对 ER 阴性乳腺癌。
