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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 Paclitaxel¹

Section of Molecular Cell Biology, Departments of Cancer Biology [L. Z., Y-K. L., W. X., M-C. H.] and Breast Medical Oncology [G. N. H.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

ABSTRACT

Overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185^neu, has been observed in tumors from breast cancer patients. We demonstrated previously that emodin, a tyrosine kinase inhibitor, suppresses tyrosine kinase activity in HER-2/neu-overexpressing breast cancer cells and preferentially represses transformation phenotypes of these cells in vitro. In the present study, we examined whether emodin can inhibit 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 inhibited tumor growth and prolonged survival in mice bearing HER-2/neu-overexpressing human breast cancer cells. Furthermore, the combination of emodin and paclitaxel synergistically inhibited the anchorage-dependent and -independent growth of HER-2/neu-overexpressing breast cancer cells in vitro and synergistically inhibited tumor growth and prolonged survival in athymic mice bearing s.c. xenografts of human tumor cells expressing high levels of p185^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 tyrosine kinase inhibitors such as emodin can inhibit the growth of HER-2/neu-overexpressing tumors in mice and also sensitize these tumors to paclitaxel. The results may have important implications in chemotherapy for HER-2/neu-overexpressing breast tumors.

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