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

Clin Cancer Res. 1999 Feb;5(2):343-53.

Abstract

Overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185neu, 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 p185neu. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Cell Division / drug effects
  • Disease Models, Animal
  • Drug Synergism
  • Emodin / therapeutic use*
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Paclitaxel / therapeutic use*
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Mas
  • Receptor, ErbB-2 / biosynthesis*
  • Tumor Cells, Cultured
  • Tyrosine / metabolism

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Emodin
  • Paclitaxel