Preventive effect of Juzen-taiho-to on endometrial carcinogenesis in mice is based on Shimotsu-to constituent.

Abstract

Juzen-taiho-to, a Kampo formula, originally consists of a mixture of Shimotsu-to and Shikunshi-to formulas together with two other crude ingredients. Juzen-taiho-to is reported to have a preventive effect on endometrial carcinogenesis in mice. Shimotsu-to exerts an inhibitory effect on estrogen-induced expression of c-fos, interleukin (IL)-1alpha and tumor necrosis factor (TNF)-alpha in uteri of ovarectomized mice. In the present study, short- and long-term experiments were designed to determine the effects of Juzen-taiho-to and Shimotsu-to on the estrogen-related endometrial carcinogenesis in mouse uteri, associated with the expression of cyclooxygenase (COX)-1 and -2. In the short-term experiment, exposure to Juzen-taiho-to or Shimotsu-to significantly reduced estradiol-17beta (E(2))-stimulated expressions of COX-2 mRNA (p<0.05) as well as the protein. However, no effects on the expression of COX-1 were observed. Shikunshi-to did not affect COX expression. In the long-term experiment, 90 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, a diet containing 0.07% Shimotsu-to and 5 ppm E(2); group 2, a diet containing 5 ppm E(2); group 3, a diet containing 0.07% Shimotsu-to; group 4 served as a control. Exposure of Shimotsu-to reduced the incidence of MNU- and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks). The above findings and our previous reports suggest that Shimotsu-to is responsible for the preventive effects of Juzen-taiho-to on estrogen-related endometrial carcinogenesis in mice, through the inhibition of estrogen-related COX-2 as well as c-fos, IL-1alpha and TNF-alpha expressions.