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

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.

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.

Conclusions: 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.