Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APC

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.