Ziyuglycoside II induces cell cycle arrest and apoptosis through activation of ROS/JNK pathway in human breast cancer cells

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.