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Int. J. Mol. Sci. 2013, 14(2), 2980-2995; doi:10.3390/ijms14022980
Article

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

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1 Tang Center for Herbal Medicine Research, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA 2 Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA 3 Section of Hematology/Oncology, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA 4 Department of Orthopaedic Surgery, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 3079, Chicago, IL 60637, USA 5 Ben May Department for Cancer Research, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA 6 Department of Medicine, University of Chicago, 900 E. 57th street, MB 9, Chicago, IL 60637, USA 7 Committee on Clinical Pharmacology and Pharmacogenomics, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA
* Author to whom correspondence should be addressed.
Received: 6 December 2012 / Revised: 24 January 2013 / Accepted: 25 January 2013 / Published: 31 January 2013
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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.
Keywords: colorectal cancer; ginsenoside; compound K; xenograft; cell cycle arrest; p53/p21 colorectal cancer; ginsenoside; compound K; xenograft; cell cycle arrest; p53/p21
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Zhang, Z.; Du, G.-J.; Wang, C.-Z.; Wen, X.-D.; Calway, T.; Li, Z.; He, T.-C.; Du, W.; Bissonnette, M.; Musch, M.W.; Chang, E.B.; Yuan, C.-S. Compound K, a Ginsenoside Metabolite, Inhibits Colon Cancer Growth via Multiple Pathways Including p53-p21 Interactions. Int. J. Mol. Sci. 2013, 14, 2980-2995.

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