Open AccessMechanisms Mediating the Synergistic Anticancer Effects of Combined γ-Tocotrienol and Celecoxib Treatment
Author(s) -
Amit B. Shirode,
Paul W. Sylvester
Publication year - 2011
Publication title -
journal of bioanalysis and biomedicine
Language(s) - English
Resource type - Journals
ISSN - 1948-593X
DOI - 10.4172/1948-593x.1000036
Subject(s) - celecoxib , protein kinase b , pharmacology , tocotrienol , prostaglandin e , prostaglandin e2 , chemistry , prostaglandin e2 receptor , prostaglandin , signal transduction , receptor , medicine , endocrinology , biochemistry , vitamin e , tocopherol , antioxidant , agonist
AIM: To characterize the intracellular signaling mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment in neoplastic +SA mouse mammary epithelial cells in vitro. METHODS: +SA mammary tumor cells in different treatment groups were maintained in serum-free defined media containing 10ng/ml EGF as a mitogen and exposed to various doses of γ-tocotrienol and celecoxib alone or in combination. After a 96 hr culture period, cells were collected and whole cell lysates were subjected to Western blot analysis to determine treatment effects on intracellular signaling proteins associated with EGF-dependent mitogenesis and survival, and prostaglandin synthesis and responsiveness. RESULTS: Treatment with high doses of γ-tocotrienol or celecoxib alone inhibited Akt activation and downstream signaling and NFκB activation. Similar treatment with γ-tocotrienol also decreased concentration and activation of ErbB2-4 receptors, whereas celecoxib only inhibited ErbB2-4 receptor activation. In contrast, combined treatment with subeffective doses of γ-tocotrienol and celecoxib resulted in a large decrease ErbB2-4 receptor levels and activation, a decrease in PGE(2) levels, and a corresponding increase in prostaglandin EP2 and EP4 receptor levels. Combined treatment also induced an increase in the prostaglandin catabolizing enzyme, PGDH. CONCLUSION: The synergistic anticancer effects of combined low dose γ-tocotrienol and celecoxib treatment in +SA mammary tumor cells are mediated by COX-2-dependent mechanisms associated with a suppression in PGE(2) levels, as well as, COX-2-independent mechanisms associated with a reduction in ErbB2-4 receptor levels, activation, and subsequent reduction in downstream Akt and NFκB mitogenic signaling.