Anti-Invasive and Metastatic Activities of Evodiamine.

We have recently reported that evodiamine can suppress in vitro invasion and lung metastasis by colon 26-L5 carcinoma cells. To extend our study, we examine here the anti-invasive and metastatic effects of evodiamine on Lewis lung carcinoma (LLC) and B16-F10 melanoma in addition to colon 26-L5 carcinoma. Critical structures of evodiamine for the activities were also evaluated by comparison with compounds possessing structures similar to that of evodiamine. Evodiamine concentration-dependently inhibited the invasion of B16-F10, LLC and colon 26-L5 cells with IC(50) values of 2.4 micro M, 4.8 micro M and 3.7 micro M, respectively. Pre-treatment of colon 26-L5 cells with evodiamine before inoculation into mice caused significant suppression of the liver metastasis as well as the lung metastasis. Lung metastasis by LLC is also inhibited significantly by pre-exposure to evodiamine. When the anti-migratory activity of evodiamine was compared with that of evodiamine-like compounds, rutaecarpine lacking a methyl group at N-14 and a hydrogen at C-13 b exhibited much less effect than evodiamine. In addition, reserpine, having beta-configurated hydrogen at C-13 b, inhibited tumor cell migration more potently than yohimbine, having alpha-configurated hydrogen at the same position. These results suggest that evodiamine may be useful as a leading compound for agents in tumor metastasis therapy. Also, the presence of a methyl group at N-14 and the configuration of hydrogen at C-13 b may be responsible for the inhibitory activities of evodiamine.