Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells

Anticancer Res. 2010 Feb;30(2):429-37.


Background: Heterodimer cooperation between ErbB receptors has limited clinical usefulness of receptor tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib in the treatment of cancer. However, combination treatment of TKIs with gamma-tocotrienol targets multiple ErbB receptors and significantly inhibit +SA murine mammary tumor cell growth.

Materials and methods: Cell proliferation was determined by tetrazolium (MTT) assay and immunofluorescent Ki-67 staining. Western blot analysis was used to determine treatment effects on epidermal growth factor (EGF)-dependent mitogenic signaling.

Results: Combined treatment of 3 microM gamma-tocotrienol with 0.25 microM erlotinib or 0.5 microM gefitinib significantly inhibited +SA cell growth and reduced cyclin D1 and phosphorylated (active) Pdk-1, Akt, Stat3 and Stat5 levels.

Conclusion: Combined treatment of gamma-tocotrienol with erlotinib or gefitinib prevents ErbB receptor heterodimer cooperation and inhibits EGF-dependent mitogenic signaling in +SA murine mammary tumor cells. These findings strongly suggest that combination treatment may significantly improve therapeutic responsiveness in breast cancer patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Chromans / pharmacology*
  • Erlotinib Hydrochloride
  • Female
  • Gefitinib
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / metabolism
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinazolines / administration & dosage
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / drug effects*
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology


  • Chromans
  • Quinazolines
  • STAT Transcription Factors
  • Vitamin E
  • plastochromanol 8
  • Erlotinib Hydrochloride
  • Proto-Oncogene Proteins c-akt
  • Gefitinib