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论文类型：期刊论文

发表时间：2016-01-25

发表刊物：CHEMICO-BIOLOGICAL INTERACTIONS

收录刊物：SCIE、PubMed、Scopus

卷号：244

页面范围：94-104

ISSN号：0009-2797

关键字：Apoptosis; Autophagy; Breast cancer; SZC015

摘要：Breast cancer is one of the most common cancers among women with high mortality and morbidity. The present study was aimed to investigate the cytotoxic mechanism of SZC015, a synthetic oleanolic acid (OA) derivative, in MCF-7 human breast cancer cells. SZC015 reduced MCF-7 cell viability with an IC50 value of only 24.19 mu M at 24 h by activating both apoptosis and autophagy pathways. More specifically, we found that SZC015 was able to activate intrinsic apoptosis, which was proved by activations of caspase3, caspase9, release of cytochrome C, cleavage of PARP and increasing ratio of Bax/Bcl-2. SZC015 induced autophagy in MCF-7 cells evidenced by the increase of LC3II/LC3I and up-regulation of Atg5 and beclin1. Moreover, these two cell death pathways were modulated by inhibiting phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin/nuclear factor-kappa B (PI3K/Akt/mTOR/NF-kappa B), mitogen-activated protein kinase (MAPK) signaling pathways. SZC015 also induced S phase cell cycle arrest in MCF-7 cells. Furthermore, analysis of topoisomerase I (Top I) and topoisomerase II alpha (Top II alpha) proteins suggested that SZC015 may interfere the DNA topological phenomenon. The computer-assisted molecular docking study also showed SZC015 had lower interaction energy with Top I and Top IIa than that of OA. In conclusion, the current study revealed SZC015 played an important role in the regulation of autophagy and apoptosis in breast cancer cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.