Abstract
BackgroundCycloartane triterpenoids exhibited anticancer effects. This study aims to identify any potential novel anticancer cycloartane triterpenoids from Cimicifuga foetida L. rhizome (Sheng ma) and the mode of actions.MethodsCycloartane triterpenoids were isolated from the C. 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.ResultsA 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.ConclusionsADHC-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.
Highlights
The Infrared spectra (IR) spectrum displayed the presence of hydroxyl groups (3338 cm−1) and a carbonyl group (1730 cm−1)
The 1HNMR spectrum (Table 1) showed signals of cyclopropane methylene groups at δ 0.43 and 0.96 ppm, six methyl groups at δ 1.05, 1.08, 1.13, 1.20, 1.65 and 1.67 ppm; an aromatic proton at δ 4.82 ppm (d, J = 8.0 Hz), and a series of overlapped signals, which suggested that ADHC-AXpn was a cycloartane-type triterpene glycoside [12]
When the 13C-nuclear magnetic resonance (NMR) spectrum of ADHC-AXpn was compared with that of 25-AC, the signals of C-1′ and C-3′ were seen to shift to higher field by 2.6 and 2.0 ppm, while the signal of C-2′ shifted to lower field
Summary
This study aims to identify any potential novel anticancer cycloartane triterpenoids from Cimicifuga foetida L. rhizome (Sheng ma) and the mode of actions. Cycloartane triterpenoid (CATP) are triterpene glycosides with a unique structural C-19 angular methyl (Fig. 1), are distributed in plants of several genuses, such as Astragalus, Cimicifuga, and Thalictrum [2, 3]. Several CATPs isolated from plants exhibited potential anticancer activities [4,5,6,7]. C. foetida contains many CATPs [9, 10], and some CATPs from the Cimicifuga genus possessed anti-cancer effects in vivo and in vitro [4,5,6]. Previous research focused on isolation and structure identification rather than biological activity. Our earlier research associated CATP anticancer activity with apoptosis induction and cell cycle arrest in tumor cells [4, 5], but respective biological pathways have not yet investigated
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