Compound K, a Ginsenoside Metabolite, Inhibits Colon Cancer Growth via Multiple Pathways Including p53-p21 Interactions

Abstract

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 cancers. However, the mechanisms are not completely understood, especially in colorectal cancer (CRC). A xenograft tumor model was used first to examine the anti-CRC effect of CK in vivo. Then, multiple in vitro assays were applied to investigate the anticancer effects of CK including antiproliferation, apoptosis and cell cycle distribution. In addition, a qPCR array and western blot analysis were executed to screen and validate the molecules and pathways involved. We observed that CK significantly inhibited the growth of HCT-116 tumors in an athymic nude mouse xenograft model. CK significantly inhibited the proliferation of human CRC cell lines HCT-116, SW-480, and HT-29 in a dose- and time-dependent manner. We also observed that CK induced cell apoptosis and arrested the cell cycle in the G1 phase in HCT-116 cells. The processes were related to the upregulation of p53/p21, FoxO3a-p27/p15 and Smad3, and downregulation of cdc25A, CDK4/6 and cyclin D1/3. The major regulated targets of CK were cyclin dependent inhibitors, including p21, p27, and p15. These results indicate that CK inhibits transcriptional activation of multiple tumor-promoting pathways in CRC, suggesting that CK could be an active compound in the prevention or treatment of CRC.

TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol

“…The expression of cyclin E2 peaks at the G1-S phase and exhibits a pattern of tissue specificity distinct from that of cyclin E1 (34, 35). In addition, although not involved in top 20 upregulated gene list, CDKN1A (p21) was significantly upregulated by the treatment of PPD, which is consistent with previous reports that PPD analogs increased p21 expression in protein level (36, 37). The p21 binds to all G1/S cyclin-cdk complexes, in preventing the G1-S transition, leading to G1 arrest and inhibiting cell proliferation (38).…”

Determination of American ginseng saponins and their metabolites in human plasma, urine and feces samples by liquid chromatography coupled with quadrupole time-of-flight mass spectrometry

“…Our previous research data showed that compound K is a primary metabolite of American ginseng root [21]. A narrow mass window of 0.01 Da to restructure the EICs of ginsenoside Rb 1 and compound K of the typical plasma sample is shown in Fig.…”

Ginsenosides and their metabolites: a review of their pharmacological activities in the skin

“…Most ginsenosides are converted to their metabolites in the gastrointestinal tract. Many studies have reported similar or superior effects of metabolites in comparison to their parent ginsenosides [6,34,69]. Further studies and deeper insights into the interactions between ginsenoside compounds and their metabolites with cellular targets will facilitate the development of novel medicinal and cosmeceutical products.…”

“…Indeed, various studies have outlined its biological activity and underlying mechanisms of action [16,28,59,65]. The anticancer activity of compound K has been studied for several decades [29,63,69]. In a colon cancer model, compound K induced both apoptotic and autophagic pathways via ROS generation and c-Jun NH2-terminal kinase activation [29].…”