Abstract B28: Chemoprevention of colorectal cancer: Does American ginseng play a role?

Abstract

Abstract Colorectal cancer (CRC) is one of the most common cancers worldwide. Based on the fact that many anticancer agents are developed from botanical sources, there is a significant untapped resource to be found in natural products. American ginseng (Panax quinquefolius L.) is a commonly used herbal medicine in the United States. Several epidemiological studies have suggested that ginseng can prevent or treat human malignancies. However, the chemopreventive effects of ginseng and its active compounds on CRC are largely unknown. It is believed that the bioactive constituents of ginseng are a group of triterpenoid glycosides, or ginsenosides. After oral ingestion, ginsenosides can be transformed to their metabolites in the gut before absorption into the body. We performed a pilot clinical study to evaluate the absorption of ginseng compounds. Six healthy human subjects received a single oral dose of 10 g of American ginseng root powder, and blood samples were collected at 0-12 h. Plasma levels of ginsenosides and their metabolites were determined with ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC/TOF-MS). To validate the data observed in the clinical study, we performed an in vitro biotransformation study on ginseng extract using human microbiota. To test the biological efficacy of ginsenosides and their metabolites, a panel of human CRC wells was used to determine their antiproliferative efficacy. The in vivo antitumor potential and involved mechanisms of the active metabolites were also evaluated. Ginsenosides Rb1, Rd, Rg2 and compound K (CK) were detected in human plasma at different points in time. The peak level of Rb1 was 19.90 ± 5.43 ng/ml at 4 h, and CK was detected from 7 h to 12 h with 7.32 ± 1.35 ng/ml at 12 h. Since the last time point was at 12 h, the peak level of CK was not observed. The areas under the concentration curves (AUC) from 0 to 12 h were 155.0 ± 19.5 ng·h/ml for Rb1 and 26.4 ± 6.4 ng·h/ml for CK, respectively. The delayed tmax of CK compared to the parent compounds suggested that intestinal microbiota may be critical in transforming Rb1 to CK. To test this hypothesis, fecal microflora from a healthy human subject was employed to transform the ginseng extract. After LC/Q-TOF-MS analysis, 25 metabolites were identified from biotransformed ginseng extract, in which the three most abundant metabolites were ginsenosides Rg3, F2 and CK. This result supported our clinical observations. Subsequent biological evaluation indicated that CK had significant antiproliferative effects in HCT-116, SW-480 and HT-29 human CRC cells at concentrations of 30-50 μM. At the same concentrations, Rb1 did not have any effect. In vivo data showed that the intraperitoneal administration of CK significantly inhibited CRC xenograft tumor growth, and the higher dose (30 mg/kg) exhibited a stronger antitumor effect (P < 0.01) than the lower dose (15 mg/kg) (P < 0.05). We observed that CK arrested the cell cycle in the G1 phase and induced cell apoptosis. CK-induced CRC cell death is mediated by multiple pathways, including ATM/p53-p21, PI3K/Akt and TGF-β. In conclusion, data from our in vitro, in vivo and clinical studies suggested that the intestinal microbiota metabolite CK, not Rb1, could be a promising ginseng-derived compound to prevent CRC. American ginseng plays a key role in colorectal cancer chemoprevention (Grant support: NIH/NCCAM AT004418 and AT005362). Citation Format: Chong-Zhi Wang, Samantha Anderson, Chun-Su Yuan. Chemoprevention of colorectal cancer: Does American ginseng play a role? [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B28.