Daikenchuto (TU‐100) Suppresses Tumor Development in the Azoxymethane and APC^min/+ Mouse Models of Experimental Colon Cancer

Abstract

Chemopreventative properties of traditional medicines, Kampo and underlying mechanisms of action have not been well explored. This study demonstrates that daikenchuto (TU-100), comprised of ginger, ginseng, and Japanese pepper (50/30/20 by weight), effectively suppresses development and progression of intestinal tumors in the azoxymethane (AOM) and the APCmin/+ mouse models. TU-100 was included in the diet. TU-100 was provided after first of 6, biweekly AOM injections, mice sacrificed at 30 weeks. APCmin/+ mice were fed without or with TU-100 starting at 6 weeks, sacrificed at 24 weeks. In both models, dietary TU-100 decreased tumor size. In the APC min/+ model, the number of small intestinal tumors was also significantly decreased, whereas in the AOM model, both TU-100 and Japanese ginseng decreased tumor numbers. TU-100 and ginseng decreased Ki67 and β-catenin immunostaining and activation of numerous transduction pathways involved in tumor initiation and progression. EGF receptor expression and stimulation/phosphorylation in vitro was investigated in Caco2BBE cells. TU-100, ginger, and 6-gingerol, but not ginseng, ginsenoside Rb1 and the bacterial metabolite compound K, nor Japanese pepper suppressed EGF receptor induced Akt activation. TU-100 and ginseng and to a lesser extent ginger or 6-gingerol, but not Japanese pepper, ginsenoside Rb1 or compound K inhibited EGF activation of ERK1/2. In conclusion, TU-100 and some of its components and metabolites inhibit tumor progression in two mouse models of colon cancer by blocking downstream pathways of EGF receptor activation.

Ginsenoside Rb1 promotes intestinal epithelial wound healing through extracellular signal‐regulated kinase and Rho signaling

“…Therefore, we focused on the direct effect of GRb1 on intestinal epithelial cells by using a wound‐healing assay. Several investigations have described the many pharmacological properties of ginsenosides, including anti‐ulcer, anti‐tumor, anti‐inflammation, anti‐oxidant, and anti‐fatigue effects . Watanabe et al .…”

“…Several investigations have described the many pharmacological properties of ginsenosides, including anti-ulcer, anti-tumor, anti-inflammation, anti-oxidant, and anti-fatigue effects. [25][26][27][28][29][30][31] Watanabe et al demonstrated that GRb1-containing films significantly improved oral mucositis induced by fluorouracil and mucosal inflammation. 31 Rat gastric injury induced by HClethanol, indomethacin, and pyloric ligation was significantly reduced by oral GRb1 treatment.…”

Daikenchuto (TU‐100) alters murine hepatic and intestinal drug metabolizing enzymes in an in vivo dietary model: effects of gender and withdrawal

“…Another possibility is the role of differential gut microbiome in altered expression of DMEs and DTs (Kuno et al 2015). TU-100 is known to alter the intestinal microbiome (Hasebe et al 2016) and accumulating evidence indicate that gut microbiome plays a key role in regulating hepatic and intestinal DMEs and DTs (Einarsson et al 1973;Overvik et al 1990;Nugon-Baudon et al 1998;Hooper et al 2001;Bjorkholm et al 2009;Meinl et al 2009;Toda et al 2009;Saad et al 2012;Selwyn et al 2015). For example, Cyp activity measured by the microsomal metabolism of steroids was shown to be lower in the liver of germ-free rats as compared with conventionally raised (Einarsson et al 1973).…”

“…TU-100 was included in AIN-76A at 15 g TU-100/kg diet (1.5% wt/ wt) (Harlan Teklad; TD.110333). This dosage of TU-100 was determined previously to obtain similar blood concentrations of major TU-100 ingredients in mice to the human data Kono et al 2013;Ueno et al 2014;Watanabe et al 2015;Hasebe et al 2016). For the present studies, doses of 0.75% and 3.0% wt/wt TU-100 in the diet were also used to assess its dosedependency.…”

“…First, TU-100 is consumed over long periods of time and effects may take months and continued consumption is required for maintained effects. A previous study on intestinal microbiome effects of TU-100 demonstrated that changes were observed only after many weeks of ingestion (Hasebe et al 2016). Second, the intestinal microbiome changes may be important for alterations of DMEs and DTs as intestinal bacteria have been determined to modulate their expression (Einarsson et al 1973;Nugon-Baudon et al 1998;Hooper et al 2001).…”