Tyrosine kinase inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells in athymic mice and sensitizes these cells to the inhibitory effect of paclitaxel

Overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185(neu), has been observed in tumors from breast cancer p atients. We demonstrated previously that emodin, a tyrosine kinase inhibito r, suppresses tyrosine kinase activity in HER-2/neu-overexpressing breast c ancer cells and preferentially represses transformation phenotypes of these cells in vitro. In the present study, we examined whether emodin can inhib it the growth of HER-2/neu-overexpressing tumors in mice and whether emodin can sensitize these tumors to paclitaxel, a commonly used chemotherapeutic agent for breast cancer patients. We found that emodin significantly inhib ited tumor growth and prolonged survival in mice bearing HER-2/neu-overexpr essing human breast cancer cells, Furthermore, the combination of emodin an d paclitaxel synergistically inhibited the anchorage-dependent and -indepen dent growth of HER-2/neu-overexpressing breast cancer cells in vitro and sy nergistically inhibited tumor growth and prolonged survival in athymic mice bearing s.c. xenografts of human tumor cells expressing high levels of p18 5(neu), Both immunohistochemical staining and Western blot analysis showed that emodin decreases tyrosine phosphorylation of HER-2/neu in tumor tissue . Taken together, our results suggest that the tyrosine kinase activity of HER-2/neu is required for tumor growth and chemoresistance and that tyrosin e kinase inhibitors such as emodin can inhibit the growth of HER-2/neu-over expressing tumors in mice and also sensitize these tumors to paclitaxel, Th e results may have important implications in chemotherapy for HER-2/neu-ove rexpressing breast tumors.