Abstract
AG36 is the biotransformation product of triterpenoid saponin from Ardisia gigantifolia stapf. In this study, the antitumor activity and underlying molecular mechanisms of AG36 against human breast MCF-7, MDA-MB-231, and SK-BR-3 cancer cells were investigated. AG36 inhibited the viability of MCF-7, MDA-MB-231, and SK-BR-3 cells in a dose and time-dependent manner, with an IC50 of approximately 0.73, 18.1, and 23.4 μM at 48 h, respectively. AG36 obviously induced apoptosis and G2/M arrest of all the three breast cancer cells. Moreover, AG36 decreased the protein expression of cycle regulatory proteins cyclin B1 or cyclin D1. In MCF-7 and MDA-MB-231 cells, AG36 strongly increased the cleaved caspase-3 and -8 protein expressions, while in SK-BR-3 cells, AG36 only increased the protein expression of cleaved caspase-3. In all the three breast cancer cells, the ratio of Bax/Bcl-2 and cytosolic cytochrome c content increased significantly compared with control group. The death receptor-related proteins Fas/FasL, TNFR1, and DR5 were detected by Western blot, it showed that different breast cancer cells activated the death receptor-mediated extrinsic caspase-8 pathway through different receptors. In addition, the caspase-8 inhibitor z-IETD-fmk could significantly block AG36-triggered MCF-7 cells apoptosis. The in vivo studies showed that AG36 significantly inhibited the growth of MCF-7 xenograft tumors in BALB/c nude mice comparing with control. In conclusion, AG36 inhibited MCF-7, MDA-MB-231, and SK-BR-3 cells proliferation by the intrinsic mitochondrial and the extrinsic death receptor pathways and AG36 might be a potential breast cancer therapeutic agent.
Highlights
The rhizome of Ardisia gigantifolia stapf. is a traditional Chinese medicine used as an expectorant for the treatment of traumatic injury, rheumatism, muscles, and bones pain
To screen the potential cytotoxic effect of AG36 against breast cancer, we examined the effect of AG36 on cell proliferation in MCF-7, MDA-MB-231, and SK-BR-3 cancer cells by MTT assay
In order to determine whether decreased proliferation and cell viability were associated with apoptosis, the apoptotic effects of AG36 on MCF7 cells were investigated using annexin-V/PI double staining by flow cytometry
Summary
The rhizome of Ardisia gigantifolia stapf. is a traditional Chinese medicine used as an expectorant for the treatment of traumatic injury, rheumatism, muscles, and bones pain. Is a traditional Chinese medicine used as an expectorant for the treatment of traumatic injury, rheumatism, muscles, and bones pain. It is an evergreen dwarf shrub mostly distributed in the provinces of Guangxi, Jiangxi, and Fujian in China (Jiangsu New Medicinal College, 2001). AG36 Inhibits Breast Cancer Cells cyclamiretin A 3β-O-{α-L-rhamnopyranosyl-(1→3)-[β-Dxylopyranosyl-(1→2)]-β-D-glucopyranosyl-(1→4)-[β-D-glucopyranosyl-(1→2)]-α-L-arabinopyranoside} (AG4) had prominent cytotoxicity against MCF-7 cells (Zheng et al, 2013). The structure of AG36 is similar with that of AG4, but with four-sugar units at C-3 (Figure 1), and AG36 showed better cytotoxicity than AG4 against human breast cancer MCF-7 cells
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