title: Ginsenoside compound K, not Rb1, possesses potential chemopreventive             activities in human colorectal cancer.
abstract: Ginsenoside compound K (C-K) is an intestinal microbiota metabolite of ginsenoside Rb1, a major constituent in American ginseng. However, previous ginseng anti-cancer observations were largely focused on ginseng parent compounds but not metabolites, and anti-colorectal cancer studies on C-K were limited. This study investigated the anti-proliferative effects of C-K when compared to those of Rb1, and the related mechanisms of action, in HCT-116 and SW-480 colorectal cancer cells. The effects of Rb1 and C-K on the proliferation of HCT-116 and SW-480 human colorectal cancer cells were compared using an MTS assay. Cell cycle and cell apoptosis were assayed using flow cytometry. Enzymatic activities of caspases were determined by colorimetric assay, and interactions of C-K and caspases were explored by docking analysis. C-K showed significant anti-proliferative effects in HCT-116 and SW-480 cells at concentrations of 30-50 µM. At the same concentrations, Rb1 did not show any effects, while C-K arrested the cells in the G1 phase, and significantly induced cell apoptosis. Compared to HCT-116 (p53 wild-type), the p53 mutant cell line SW-480 was more sensitive to C-K as assessed by cell cycle regulation and apoptosis induction. C-K activated expression of caspases 8 and 9, consistent with docking analysis. The docking data suggested that C-K forms hydrogen bonds with Lys253, Thr904 and Gly362 in caspase 8, and with Thr62, Ser63 and Arg207 in caspase 9. C-K, but not its parent ginsenoside Rb1, showed significant anti-proliferative and pro-apoptotic effects in human colorectal cancer cells. These results suggest that C-K could be a potentially effective anti-colorectal cancer agent.
authors.affiliation: Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chong-Zhi
authors.initials: CZ
authors.lastname: Wang
authors.forename: Guang-Jian
authors.initials: GJ
authors.lastname: Du
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wen
authors.forename: Tyler
authors.initials: T
authors.lastname: Calway
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhen
authors.forename: Mark W
authors.initials: MW
authors.lastname: Musch
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
authors.forename: Eugene B
authors.initials: EB
authors.lastname: Chang
authors.forename: Chun-Su
authors.initials: CS
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D003198:Computer Simulation; D004790:Enzyme Induction; D036145:Ginsenosides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D036145:Ginsenosides; C442759:ginsenoside Rb1; C112772:ginsenoside compound K