Initial research on
vitamin E and
cancer has focused on α-
tocopherol (αT), but recent clinical studies on
cancer-preventive effects of αT 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 γ-
tocopherol (γT), δ-
tocopherol (δT), γ-
tocotrienol (γTE), and δ-
tocotrienol (δTE), have far superior
cancer-preventive activities than does αT. These
vitamin E forms are much stronger than αT 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 κB (NF-κB) and signal transducer and activator of
transcription factor 3 (STAT3). These
vitamin E forms, but not αT, cause pro-death or antiproliferation effects in
cancer cells via modulating various signaling pathways, including
sphingolipid metabolism. Unlike αT, 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, γT, δT, γTE, and δTE, but not αT, 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 γT, δT, γTE, and δTE 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.