Natural forms of vitamin E and metabolites—regulation of cancer cell death and underlying mechanisms

Abstract

The disappointing results from large clinical studies of α‐tocopherol (αT), the major form of vitamin E in tissues, for prevention of chronic diseases including cancer have cast doubt on not only αT but also other forms of vitamin E regarding their role in preventing carcinogenesis. However, basic research has shown that specific forms of vitamin E such as γ‐tocopherol (γT), δ‐tocopherol (δT), γ‐tocotrienol (γTE) and δ‐tocotrienol (δTE) can inhibit the growth and induce death of many types of cancer cells, and are capable of suppressing cancer development in preclinical cancer models. For these activities, these vitamin E forms are much stronger than αT. Further, recent research revealed novel anti‐inflammatory and anticancer effects of vitamin E metabolites including 13′‐carboxychromanols. This review focuses on anti‐proliferation and induction of death in cancer cells by vitamin E forms and metabolites, and discuss mechanisms underlying these anticancer activities. The existing in vitro and in vivo evidence indicates that γT, δT, tocotrienols and 13′‐carboxychromanols have anti‐cancer activities via modulating key signaling or mediators that regulate cell death and tumor progression, such as eicosanoids, NF‐κB, STAT3, PI3K, and sphingolipid metabolism. These results provide useful scientific rationales and mechanistic understanding for further translation of basic discoveries to the clinic with respect to potential use of these vitamin E forms and metabolites for cancer prevention and therapy. © 2018 IUBMB Life, 71(4):495–506, 2019

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

“…Therefore, smaller portions of these VE forms are found in the blood and tissues, and most of these VE forms are degraded in the liver and other organs. The human serum plasma levels of α‐T are generally 20 to 25 µM (8.6‐10.8 mg/L), while those of γ‐T are much lower at 1 to 3 µM 8 . However, upon supplementation with γ‐T and δ‐T3, their plasma concentration can be increased to higher than 20 µM and 5 to 10 µM, respectively, in healthy humans 8 …”

“…This degradation pathway is illustrated in Figure 2 using γ‐T as an example. The formation of long‐chain metabolites, such as 13′‐carboxychomanols (13′‐COOHs) and 11′‐COOHs, has been observed in different experimental systems 8 . Upon supplementation of γ‐T (1 mg/kg diet), rather high levels of γ‐T 13′‐COOH, (~1 µmol/g of fecal samples) were observed 8 .…”

“…The formation of long‐chain metabolites, such as 13′‐carboxychomanols (13′‐COOHs) and 11′‐COOHs, has been observed in different experimental systems 8 . Upon supplementation of γ‐T (1 mg/kg diet), rather high levels of γ‐T 13′‐COOH, (~1 µmol/g of fecal samples) were observed 8 . Short side‐chain metabolites, γ‐ and δ‐carboxyethyl hydroxychroman (CEHC), as well as γ‐ and δ‐carboxymethylbutyl hydroxychroman (CMBHC), 21–23 are found at rather high concentrations in blood and tissues, and are excreted in the urine in conjugated forms as glucuronides and sulfates.…”

“…In 2010, we reviewed the cancer‐preventive activities of tocopherols and tocotrienols 2 . Since then, this topic has been studied by a large number of investigators and reviewed by different authors 7–12 …”

IUBMB‐Life 2019: Vitamin E—Regulatory Roles

“…As discussed in this issue (issue 71:4 ), many cellular regulatory effects of vitamin E and its metabolites have been recognized modulating apoptosis/cell survival, ferroptosis, cell proliferation, angiogenesis, lipid metabolism, membrane properties and repair, long term potentiation, signal transduction and gene expression. These cellular effects often go beyond a simple antioxidant action and most likely contribute to the beneficial regulatory effects of vitamin E observed in a number of diseases and conditions, ranging from atherosclerosis, inflammation, diabetes, obesity, infection, immune regulation, wound healing, ischemia/reperfusion injury, reproduction, age‐related macular degeneration (AMD), neurodegeneration, non‐alcoholic steatohepatitis (NASH), cancer/metastasis, senescence and aging.…”