δ-Tocotrienol suppresses tumorigenesis by inducing apoptosis and blocking the COX-2/PGE2 pathway that stimulates tumor-stromal interactions in colon cancer

Anticancer effects of delta-tocotrienol have been reported for several types of cancer, but have not been fully elucidated in colorectal cancer. We investigated the anti-proliferative effect of tocotrienols in vitro, in colon epithelial cells and stromal cells, and in vivo, in an induced colorectal cancer mouse model. Of the four isoforms tested, delta-tocotrienol exerted the most potent anti-proliferative effect on colon adenocarcinoma cells. delta-Tocotrienol reduced the nitrite and prostaglandin E-2 (PGE(2)) concentrations in mouse embryonic fibroblasts (MEFs) pretreated with delta-tocotrienol and stimulated with lipopolysaccharide (LPS) and interferon gamma. Furthermore, supernatants of LPS-stimulated MEFs promoted adenocarcinoma cell proliferation, while delta-tocotrienol treatment suppressed this effect. Additionally, a delta-tocotrienol-enriched diet significantly suppressed tumor formation in azoxymethane and dextran sulfate sodium-treated mice. Taken together, these data suggest that a delta-tocotrienol-enriched diet prevents colorectal cancer. At the molecular level, tocotrienols exert a direct anti-proliferative effect on colon adenocarcinoma cells, and an indirect, stromal cell-mediated, anti-proliferative effect. (C) 2017 Elsevier Ltd. All rights reserved.