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Compound K, a Ginsenoside Metabolite, Inhibits Colon Cancer Growth via Multiple Pathways Including p

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

 

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


Zhiyu Zhang 1,2, Guang-Jian Du 1,2, Chong-Zhi Wang 1,2, Xiao-Dong Wen 1,2, Tyler Calway 2, Zejuan Li 3, Tong-Chuan He 4, Wei Du 5, Marc Bissonnette 6, Mark W. Musch 6, Eugene B. Chang 6 and Chun-Su Yuan 1,2,7,*


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; E-Mails:

7 Committee on Clinical Pharmacology and Pharmacogenomics, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637, USA

 

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

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