Abstract
BackgroundWestern diets increase colon cancer risk. Epidemiological evidence and experimental studies suggest that ginseng can inhibit colon cancer development. In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth.MethodsMice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA.ResultsGinseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth.ConclusionsGinseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis.
Highlights
Since the microbiome is essential for compound K generation, we examined the effects of dietary ginseng on microbial diversity and effects of broad-spectrum antibiotics on compound K
Since we showed that epidermal growth factor receptors (EGFR) signals were required for Western diet to promote colonic tumorigenesis [4,5], we speculate that inhibition of this cascade plays a critical role in the chemopreventive effects of ginseng by limiting proliferation and increasing apoptosis in this model
Ginseng inhibits AOM/dextran sulfate sodium (DSS) induced colonic tumorigenesis promoted by a Western diet
Summary
In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth. Complementary and alternative medicines are widely used for a variety of health purposes Many of these agents are well tolerated and some have served as lead compounds for developing more effective anti-cancer agents. Given the requirement for EGFR in tumor promotion by Western diet, in the current study we investigated the ability of ginseng extract to inhibit colonic tumorigenesis under conditions of Western dietary stress. Azoxymethane is a pro-carcinogen that is metabolized in the liver and further metabolized in the colon to an active alkylating agent, presumably a methyl carbonium ion [20] This methyl donor leads to guanine methylations and eventually G to A transitions [21]. DSS is a polysulfated polymer that arrests colonic crypt cell re-generation leading to acute mucosal ulceration and clinical colitis that enhances tumorigenesis [22]
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