Abstract 3045: Sesamin synergistically potentiates the anticancer effects of γ-tocotrienol in mammary tumor cells

Abstract

Abstract Epidemiological studies have highlighted the ability of micronutrients in plants to reduce the risk of breast cancer. Phytochemicals can interfere with cell-signaling pathways that regulate cell proliferation and differentiation. γ-Tocotrienol is a natural form of vitamin E that displays a potent and selective anticancer activity against various mammary cell lines with no discernible toxicity toward normal cells. Sesamin is an abundant phytochemical in sesame seed oil which showed antiproliferative and antiangiogenic activity against human breast cancer cells. In addition, sesamin inhibits the metabolism of vitamin E isomers and increases their bioavailability and efficacy. Preliminary growth inhibition studies showed that combined treatment with subeffective doses of γ-tocotrienol and sesamin synergistically inhibited the growth of neoplastic murine +SA (ErbB2-positive) and human MCF-7 (luminal A, ER-positive) mammary epithelial cells, as determined by MTT assay and isobologram analysis. Additional studies were conducted to determine the intracellular mechanisms mediating the synergistic anticancer activity in +SA mammary epithelial cells. Flow cytometry analysis showed that combined treatment of γ-tocotrienol and sesamin increased the percentage of cells in G1 phase as compared to the vehicle-treated control group. Western blot studies revealed that blockade in cell cycle progression is associated with decreased expression of cyclin D1, CDK2, CDK4, CDK6, phospho-Rb, and E2F1 transcription factor, and corresponding increase in levels of the cyclin-dependent kinase inhibitor proteins, p27 and p16. Additional Western blot experiments showed that the combined γ-tocotrienol and sesamin treatment caused a marked decrease of ErbB2, ErbB3, and ErbB4 receptors phosphorylation. Furthermore, the combined low dose γ-tocotrienol and sesamin treatment was associated with a relatively large decrease in the intracellular levels of total or phosphorylated c-Raf, Mek1/2, Erk1/2, PI3K, PDK1, Akt, p-NF-κB, Jak1, Jak2, and Stat1 as compared to all other treatment groups. Additional studies were conducted to investigate whether the growth inhibitory effects of the combined treatment is associated with a concomitant activation of apoptotic pathways. Results showed that the combined γ-tocotrienol and sesamin treatment did not activate early or late apoptosis events in the cell indicating that the inhibitory effects of the combined treatment are cytostatic, but not cytotoxic. In summary, these findings indicate that sesamin synergistically increases the anticancer effects of γ-tocotrienol, and combined treatment with these agents may provide some benefits in the treatment of breast cancer in women. This study was supported by a grant from First Tech International Ltd., and the Malaysian Palm Oil Council. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3045. doi:1538-7445.AM2012-3045