Vitamin E and related tocols in cancer: Unraveling the paradox of antioxidant and pro-oxidant roles.

Vitamin E, strictly defined as α-tocopherol, exhibits a complex dual role in cancer pathogenesis through its context-dependent pro-oxidant and antioxidant activities. Other members of the tocopherol and tocotrienol families (collectively referred to as tocols) have also been extensively studied for their bioactivities. At physiological levels, certain tocols such as γ-tocopherol and δ-tocotrienol act as potent antioxidants by neutralizing reactive oxygen species, inhibiting lipid peroxidation, and activating NRF2-mediated defenses, thereby suppressing tumor initiation, proliferation, and metastasis in models of colon, breast, and prostate cancers. On the contrary, under conditions such as high concentration of vitamin E in plasma, metabolic dysregulation, and the presence of transition metals (e.g., Cu²⁺), or specific genetic backgrounds, vitamin E exerts pro-oxidant effects. However, such effects are relatively rare and more often documented in vitro than in vivo. These include promoting reactive oxygen species generation, reducing p53 expression, enhancing angiogenesis, and facilitating cancer cell survival-ultimately driving tumor progression and metastasis. Critically, vitamin E modulates ferroptosis, a regulated cell death pathway pivotal in cancer; it inhibits ferroptosis via GPX4 upregulation and NRF2 activation but may paradoxically promote it in certain settings. Clinical studies highlight isomer-specific outcomes, with tocotrienols showing promise in adjuvant therapy. The dichotomy hinges on dosage, cellular microenvironment, redox balance, and vitamin E isoform. Overall, the biological impact of vitamin E is highly context-dependent, influenced by dosage, cellular microenvironment, redox status, and the specific tocol studied. Future research must prioritize isoform-specific mechanisms, optimal dosing strategies, and interactions with conventional therapies to harness vitamin E and related tocols's anticancer potential while mitigating risks.