Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu Province, China.
Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu Province, China.
Toxicol Lett. 2014 May 16;227(1):65-73. doi: 10.1016/j.toxlet.2014.03.015. Epub 2014 Mar 28.
Ziyuglycoside II, a triterpenoid saponin compound extracted from Sanguisorba officinalis L., has been reported to have a wide range of clinical applications including anti-cancer effect. In this study, the anti-proliferative effect of ziyuglycoside II in two classic human breast cancer cell lines, MCF-7 and MDA-MB-231, was extensively investigated. Our study indicated that ziyuglycoside II could effectively induce G2/M phase arrest and apoptosis in both cell lines. Cell cycle blocking was associated with the down-regulation of Cdc25C, Cdc2, cyclin A and cyclin B1 as well as the up-regulation of p21/WAF1, phospho-Cdc25C and phospho-Cdc2. Ziyuglycoside II treatment also induced reactive oxygen species (ROS) production and apoptosis by activating the extrinsic/Fas/FasL pathway as well as the intrinsic/mitochondrial pathway. More importantly, the c-Jun NH2-terminal kinase (JNK), a downstream target of ROS, was found to be a critical mediator of ziyuglycoside II-induced cell apoptosis. Further knockdown of JNK by siRNA could inhibit ziyuglycoside II-mediated apoptosis with attenuating the up-regulation of Bax and Fas/FasL as well as the down-regulation of Bcl-2. Taken together, the cell death of breast cancer cells in response to ziyuglycoside II was dependent upon cell cycle arrest and cell apoptosis via a ROS-dependent JNK activation pathway. Our findings may significantly contribute to the understanding of the anti-proliferative effect of ziyuglycoside II, in particular to breast carcinoma and provide novel insights into the potential application of such compound in breast cancer therapy.
梓醇 II 是从地榆中提取的一种三萜皂苷化合物，据报道具有广泛的临床应用，包括抗癌作用。在这项研究中，我们广泛研究了梓醇 II 对两种经典的人乳腺癌细胞系 MCF-7 和 MDA-MB-231 的抗增殖作用。我们的研究表明，梓醇 II 可以有效地诱导这两种细胞系的 G2/M 期阻滞和细胞凋亡。细胞周期阻滞与 Cdc25C、Cdc2、细胞周期蛋白 A 和细胞周期蛋白 B1 的下调以及 p21/WAF1、磷酸化 Cdc25C 和磷酸化 Cdc2 的上调有关。梓醇 II 处理还通过激活外源性/Fas/FasL 途径和内源性/线粒体途径诱导活性氧 (ROS) 产生和细胞凋亡。更重要的是，ROS 的下游靶标 c-Jun NH2-末端激酶 (JNK) 被发现是梓醇 II 诱导细胞凋亡的关键介质。进一步通过 siRNA 敲低 JNK 可以抑制梓醇 II 介导的细胞凋亡，同时减弱 Bax 和 Fas/FasL 的上调以及 Bcl-2 的下调。总之，乳腺癌细胞对梓醇 II 的细胞死亡依赖于细胞周期阻滞和细胞凋亡，通过 ROS 依赖性 JNK 激活途径。我们的研究结果可能对理解梓醇 II 的抗增殖作用有重要贡献，特别是对乳腺癌，并为该化合物在乳腺癌治疗中的潜在应用提供了新的见解。
