Combined γ-Tocotrienol and Erlotinib/Gefitinib Treatment Suppresses Stat and Akt Signaling in Murine Mammary Tumor Cells

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 +S...

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Bibliographic Details
Published in:Anticancer research 2010-02, Vol.30 (2), p.429-437
Main Authors: BACHAWAL, Sunitha V, WALI, Vikram B, SYLVESTER, Paul W
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Blotting, Western
Cell Proliferation - drug effects
Chromans - pharmacology
Erlotinib Hydrochloride
Female
Gynecology. Andrology. Obstetrics
Mammary gland diseases
Mammary Neoplasms, Animal - drug therapy
Mammary Neoplasms, Animal - metabolism
Mammary Neoplasms, Animal - pathology
Medical sciences
Mice
Proto-Oncogene Proteins c-akt - metabolism
Quinazolines - administration & dosage
Signal Transduction - drug effects
STAT Transcription Factors - metabolism
Tumors
Vitamin E - analogs & derivatives
Vitamin E - pharmacology
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Summary: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. 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. 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. 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.
ISSN:0250-7005
1791-7530