Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells

Sylvester PW, Shah SJ.

Front Biosci. 2005 Jan 1;10:699-709. Print 2005 Jan 1.

Tocopherols and tocotrienol represent the two subgroups within the vitamin E family of compounds, but only tocotrienols display potent anticancer activity at doses that have little or no effect on normal cell growth or function. Tocotrienols are potent antioxidants, but antitumor activity is independent of antioxidant activity. The exact reason why tocotrienols are more potent than tocopherols is not completely understood, but at least part of the reason is because of greater cellular accumulation. Furthermore, dose-response studies show that growth inhibitory doses of tocotrienolsare 5-6 times lower than their corresponding lethal doses, suggesting that the antiproliferative and cytotoxic effects of tocotrienols are mediated through different mechanisms. Recent studies showed that tocotrienol-induced programmed cell death (apoptosis) results from the activation of specific intracellular cysteine proteases (caspases) associated with death receptor activation and signal transduction. Furthermore, combined treatment with specific caspase inhibitors blocked the cytotoxic effects of tocotrienols in malignant mammary epithelial cells. In contrast, tocotrienolinhibition of cell proliferation appears to involve the suppression of multiple hormone- and growth factor-receptor mitogenic signaling pathways. Although additional studies are required to clarify the intracellular mechanisms mediating the anticancer effects of tocotrienols, experimental evidence strongly suggests that dietary supplementation of tocotrienols may provide significant health benefits in lowering the risk of breast cancer in women.

Our understanding of the role of vitamin E in human nutrition, health, and disease has broadened and changed over the past two decades. Viewed initially as nature’s most potent lipid-soluble antioxidant (and discovered for its crucial role in mammalian reproduction) we have now come to realize that vitamin E action has many more facets, depending on the physiological context. Although mainly acting as an antioxidant, vitamin E can also be a pro-oxidant; it can even have nonantioxidant functions: as a signaling molecule, as a regulator of gene expression, and, possibly, in the prevention of cancer and atherosclerosis. Since the term vitamin E encompasses a group of eight structurally related tocopherols and tocotrienols, individual isomers have different propensities with respect to these novel, nontraditional roles. The particular beneficial effects of the individual isomers have to be considered when dissecting the physiological impact of dietary vitamin E or supplements (mainly containing only the alpha-tocopherol isomer) in clinical trials. These considerations are also relevant for the design of transgenic crop plants with the goal of enhancing vitamin E content because an engineered biosynthetic pathway may be biased toward formation of one isomer. In contrast to the tremendous recent advances in knowledge of vitamin E chemistry and biology, there is little hard evidence from clinical and epidemiologic studies on the beneficial effects of supplementation with vitamin E beyond the essential requirement.

Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not?

Barry Halliwell, Joseph Rafter, and Andrew Jenner

Am J Clin Nutr. 2005 Jan;81(1 Suppl):268S-276S.

Foods and beverages rich in phenolic compounds, especially flavonoids, have often been associated with decreased risk of developing several diseases. However, it remains unclear whether this protective effect is attributable to the phenols or to other agents in the diet. Alleged health-promoting effects of flavonoids are usually attributed to their powerful antioxidant activities, but evidence for in vivo antioxidant effects of flavonoids is confusing and equivocal. This may be because maximal plasma concentrations, even after extensive flavonoid intake, may be low (insufficient to exert significant systemic antioxidant effects) and because flavonoid metabolites tend to have decreased antioxidant activity. Reports of substantial increases in plasma total antioxidant activity after flavonoid intake must be interpreted with caution; findings may be attributable to changes in urate concentrations. However, phenols might exert direct effects within the gastrointestinal tract, because of the high concentrations present. These effects could include binding of prooxidant iron, scavenging of reactive nitrogen, chlorine, and oxygen species, and perhaps inhibition of cyclooxygenases and lipoxygenases. Our measurements of flavonoids and other phenols in human fecal water are consistent with this concept. We argue that tocopherols and tocotrienols may also exert direct beneficial effects in the gastrointestinal tract and that their return to the gastrointestinal tract by the liver through the bile may be physiologically advantageous.

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