Abstract 1685: Ginsenoside compound K inhibits colorectal tumorigenesis via multiple pathways including ATM/p53-p21

Abstract

Abstract To date, colorectal cancer (CRC) remains one of the most prevalent malignancies in the United States. Health benefits derived from medicinal plants have been investigated for years. Ginseng has been shown to induce diverse pharmacological effects mediated predominantly by saponins, a type of ginsenoside contained in ginseng. Compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, has been shown to inhibit cell growth in a variety of tumors. However, the detailed mechanism, especially the effects of CK on cell cycle regulation in CRC cells, has not been examined. In addition, it is uncertain whether CK can inhibit colorectal tumor growth in vivo. In this study, we observed that CK significantly inhibited the growth of HCT-116 cells in athymic nude mouse xenograft models. Quantitative analysis revealed that CK significantly inhibited xenograft tumor growth from the 3rd week after CK administration (p<0.001); the higher dose (30mg/kg) of CK treatment exhibited a stronger effect than the lower dose (15mg/kg)(p<0.001). Using MTS assay, we showed that CK significantly inhibited the viability of human colorectal cancer cell lines HCT-116, HT-29 and SW480 in a dose- and time-dependent manner(with IC50 at around 10, 25, and 25uM respectively, p<0.01). In a flow cytometry assay, it was shown that CK could significantly induce HCT-116 cell apoptosis and arrest the cell cycle in the G1 phase. By screening with cell cycle and cell signal PCR arrays, some of the most relevant genes(such as CDKs/cyclins, BCL2, E2F4, p21CDKN1A, p15CDKN2B, TP53, etc.) and signal transduction pathways(such as p53, TGF-β, PI3K/AKT, pathways) were shown to be transcriptionally regulated after CK exposure. Western blots showed that the major regulated targets of CK are cyclin dependent inhibitors, including p21, p27, and p15. CK-induced colorectal cancer cell apoptosis and cell cycle arrest were related to the up-regulation of p53/p21, FoxO3a-p27/p15, Smad3, etc and down-regulation of cdc25A, CDK4/6 and cyclin D1/3 as well. Taken together, the results indicate that CK inhibits transcriptional activation of multiple tumor-promoting pathways in colorectal cancer, which suggest that CK could be useful for the prevention or treatment of CRC. Key words: Colorectal cancer, Ginsenoside, xenograft tumor, p53/p21, cell cycle arrest Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1685. doi:1538-7445.AM2012-1685