Mechanisms Mediating the Synergistic Anticancer Effects of Combined ÃÂ³-Tocotrienol and Celecoxib Treatment
Amit B. Shirode and Paul W. Sylvester*
College of Pharmacy, University of Louisiana at Monroe, 700 University Ave., Monroe, LA 71209
- *Corresponding Author:
- Dr. Paul W. Sylvester
College of Pharmacy
700 University Avenue
University of Louisiana at Monroe
Monroe, LA 71209-0470
Tel: 318-342- 1958
E-mail: [email protected]
Received Date: December 02, 2010; Accepted Date: January 08, 2011; Published Date: January 10, 2011
Citation: Shirode AB, Sylvester PW (2011) Mechanisms Mediating the Synergistic Anticancer Effects of Combined γ-Tocotrienol and Celecoxib Treatment. J Bioanal Biomed 3: 001-007. doi: 10.4172/1948-593X.1000036
Copyright: © 2011 Shirode AB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Aim: To characterize the intracellular signaling mechanisms mediating the synergistic anticancer effects of combined ?-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 ? -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 ?-tocotrienol or celecoxib alone inhibited Akt activation and downstream signaling and NF?B activation. Similar treatment with ?-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 ?-tocotrienol and celecoxib resulted in a large decrease ErbB2-4 receptor levels and activation, a decrease in PGE2 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 ?-tocotrienol and celecoxib treatment in +SA mammary tumor cells are mediated by COX-2-dependent mechanisms associated with a suppression in PGE2 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 NF?B mitogenic signaling.