Investigating Delta Tocopherol as a Novel Dietary Bladder Cancer Chemopreventive Agent

Vitamin E has been the subject of numerous basic and clinical research studies for cancer chemoprevention, which have shown widely varying results. At present, the NIH Office of Dietary Supplements does not consider there to be sufficient evidence for the use of Vitamin E supplementation for cancer prevention. The heterogeneous nature of Vitamin E and the differences in the anti-cancer activities of its components suggests that the study of individual tocopherols may yield more definitive and encouraging results. Bladder cancer (BCa) presents an ideal opportunity for the evaluation of tocopherols as novel chemopreventive agents. While a majority of newly diagnosed BCa cases are localized and confined to the initiation site on the interior urothelial lining, the high rate of recurrence necessitates long-term follow-up and increases the need for novel agents that can prevent new tumor initiation. As natural products already present in the diet, with a known safety profile, tocopherols are excellent candidates for application as dietary chemopreventive agents to reduce the recurrence rate of BCa and improve treatment outcomes. In this study, I demonstrate that delta-tocopherol is more effective than either of the more common alpha- or gamma- tocopherols at inducing apoptosis in human BCa cell lines. I identified the cause of this effect to be induction of endoplasmic reticulum (ER) stress and the unfolded protein response, leading to death receptor 5 mediated apoptosis. Additionally, delta tocopherol treated cells exhibited an autophagy-like phenotype which, when investigated further, provided novel evidence of endoplasmic reticulum specific, ER stress-related autophagy that remains an emerging field of study. Both xenograft and transgenic mouse studies have confirmed the strong anti-tumor and anti-tumorigenesis efficacy of dietary delta tocopherol administration both at the primary tumor initiation site and at distant sites, with no observed negative side effects. As the first study of delta tocopherol as an individual chemopreventive agent in BCa, these results suggest strong potential for the future development and clinical application of dietary delta tocopherol supplementation to improve the lives and treatment outcomes of BCa patients