ABSTRACT: Initial research on vitamin E and cancer has focused on ?-tocopherol (?T), but recent clinical studies on cancer-preventive effects of ?T supplementation have shown disappointing results, which has led to doubts about the role of vitamin E, including different vitamin E forms, in cancer prevention. However, accumulating mechanistic and preclinical animal studies show that other forms of vitamin E, such as ?-tocopherol (?T), ?-tocopherol (?T), ?-tocotrienol (?TE), and ?-tocotrienol (?TE), have far superior cancer-preventive activities than does ?T. These vitamin E forms are much stronger than ?T in inhibiting multiple cancer-promoting pathways, including cyclo-oxygenase (COX)- and 5-lipoxygenase (5-LOX)-catalyzed eicosanoids, and transcription factors such as nuclear transcription factor ?B (NF-?B) and signal transducer and activator of transcription factor 3 (STAT3). These vitamin E forms, but not ?T, cause pro-death or antiproliferation effects in cancer cells via modulating various signaling pathways, including sphingolipid metabolism. Unlike ?T, these vitamin E forms are quickly metabolized to various carboxychromanols including 13'-carboxychromanols, which have even stronger anti-inflammatory and anticancer effects than some vitamin precursors. Consistent with mechanistic findings, ?T, ?T, ?TE, and ?TE, but not ?T, have been shown to be effective for preventing the progression of various types of cancer in preclinical animal models. This review focuses on cancer-preventive effects and mechanisms of ?T, ?T, ?TE, and ?TE in cells and preclinical models and discusses current progress in clinical trials. The existing evidence strongly indicates that these lesser-known vitamin E forms are effective agents for cancer prevention or as adjuvants for improving prevention, therapy, and control of cancer.
