Novel cycloartane triterpenoid from Cimicifuga foetida (Sheng ma) induces mitochondrial apoptosis via inhibiting Raf/MEK/ERK pathway and Akt phosphorylation in human breast carcinoma MCF-7 cells. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Sun, Hai-yan; Liu, Bei-bei; Hu, Jian-yang; Xu, Li-jia; Chan, Shun-wan; Chan, Chi-on; Mok, Daniel; Zhang, Dong-mei; Ye, Wen-cai; Chen, Si-bao
• Is Part Of: Chinese medicine. Volume 11:Issue 1(2016)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-12
• Subjects: Medicine, Chinese -- Periodicals; Evidence-based medicine -- China -- Periodicals; Medicine, Experimental -- Periodicals; 610.95105
• DOI: 10.1186/s13020-015-0073-6
• Languages: English
• ISSNs: 1749-8546

Abstract

Abstract Background Cycloartane triterpenoids exhibited anticancer effects. This study aims to identify any potential novel anticancer cycloartane triterpenoids fromCimicifuga foetida L. rhizome (Sheng ma ) and the mode of actions. Methods Cycloartane triterpenoids were isolated from theC. foetida rhizome by a series of column chromatography and identified by IR, MS and NMR. Their anticancer effects on several human cancer cell lines, MCF-7, HepG2, HepG2/ADM, HeLa, and PC3, and normal human mammary epithelial cells MCF10A were investigated by colony formation and MTT assays. Morphological analysis of apoptosis induction was performed by acridine orange/ethidium bromide dual-staining and Hoechst 33258 nuclear staining. The cell-cycle profile and annexin V staining were evaluated by flow cytometry. Apoptosis were investigated by measuring changes in mitochondrial membrane potential and analyzing expression of cell cycle- and apoptosis-related proteins in MCF-7 cells by Western blotting. Results A novel cycloartane triterpenoid, 25-O -acetyl-7, 8-didehydrocimigenol-3-O -β -d -(2-acetyl)xylopyranoside (ADHC-AXpn), together with the known 7, 8-didehydrocimigenol-3-O -β -d -xylopyranoside (DHC-Xpn) were isolated. MCF-7 growth was significantly inhibited by ADHC-AXpn in a dose- and time-dependent manner (IC50 : 27.81 µM at 48 h;P = 0.004 vs. control at 25 μM for 48 h treatment), and ADHC-AXpn was selectively cytotoxic for cancerous cells (MCF-7, HepG2/ADM, HepG2 and HELA cells) based on its higher IC50 values for normal cells MCF10A (IC50 : 78.63 µM at 48 h) than for tumor cells. In MCF-7 cells, ADHC-AXpn induced G2 /M cell cycle arrest by mediating cyclin-B1, and CDK1 and its phosphorylation; and induced apoptosis through the mitochondrial-mediated apoptotic pathway, with inhibition of Akt activation. As ADHC-AXpn suppressed phosphorylation of ERK1/2, Raf and Akt proteins in MCF-7 cells, its apoptotic effect might be associated with Raf/MEK/ERK signaling and Akt activation. Conclusions ADHC-AXpn significantly suppressed the growth of MCF-7 cells, induced mitochondrial apoptosis and cell-cycle arrest, and inhibited Raf/MEK/ERK signaling pathway and Akt phosphorylation.