%0 Journal Article
%T Enhanced antiproliferative and apoptotic response to combined treatment of ¦Ã-tocotrienol with erlotinib or gefitinib in mammary tumor cells
%A Sunitha V Bachawal
%A Vikram B Wali
%A Paul W Sylvester
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-84
%X Highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined media containing 10 ng/ml EGF as a mitogen. Cell viability wase determined by MTT assay, whereas Western blot and immunofluorescent staining was used to determine treatment effects on ErbB receptor subtype level and activation. Treatment-induced apoptosis was determined using annexin V staining and Western blot analysis of cleaved caspase-3 and PARP levels.Treatment with 3.5 ¦ÌM ¦Ã-tocotrienol, 0.5 ¦ÌM erlotinib or 1.0 ¦ÌM gefitinib alone, significantly inhibited +SA tumor cell growth. Combined treatment with subeffective doses of erlotinib (0.25 ¦ÌM) or gefitinib (0.5 ¦ÌM) with subeffective doses of ¦Ã-tocotrienol (0.5-3.0 ¦ÌM) significantly inhibited the growth and induced apoptosis in a dose-responsive manner. Trastuzumab treatment alone or in combination had no effect on +SA cell growth and viability. Combined treatment of ¦Ã-tocotrienol with erlotinib or gefitinib also cause a large decrease in ErbB3, ErbB4, and to a lesser extent ErbB2 receptor levels, and EGF-dependent ErbB2-4 tyrosine phosphorylation (activation), but had no effect on ErbB1 receptor levels or activation.Combination treatment of ¦Ã-tocotrienol with specific ErbB receptor inhibitors is more effective in reducing mammary tumor cell growth and viability than high dose monotherapy, suggesting that targeting multiple ErbB receptors with combination therapy may significantly improve the therapeutic response in breast cancer patients.¦Ã-Tocotrienol is a member of the vitamin E family of compounds that displays potent anticancer activity at treatment doses that have little or no effect on normal cell function or viability [1-4]. Studies have shown that the growth inhibitory effects of ¦Ã-tocotrienol result from a suppression in EGF-dependent ErbB3 receptor activation and subsequent reduction in phosphatidylinositol 3-kinase (PI3K)/Akt mitogenic signaling [5]. EGF-receptors belong to the HER (human) or ErbB (mouse
%U http://www.biomedcentral.com/1471-2407/10/84