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.

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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Lack of oxidative stress in a selenium deficient area in Ivory Coast–potential nutritional antioxidant role of crude palm oil

Tiahou G, Maire B, Dupuy A, Delage M, Vernet MH, Mathieu-Daudé JC, Michel F, Sess ED, Cristol JP.

Eur J Nutr. 2004 Dec;43(6):367-74. Epub 2004 Oct 20.

BACKGROUND:Previous studies have described an important selenium deficiency in a mountain region (Glanle) in the west of Ivory Coast.

AIM OF THE STUDY:To assess the antioxidant capacity of subjects from a selenium deficient area in Ivory Coast (Glanle region).

METHODS:This study involved 57 subjects, 18 to 69 years old, living in the Glanle region and 56 healthy controls living in the southern coastal region (Bodou). In the Glanle region families consume basically a vegetarian and crude palm oil diet, whereas in the Bodou region, families eat a fish-based diet with principally refined palm oil. Fasting blood samples were collected to assess the following parameters: lipid status (plasma total lipids; total-, HDL and LDL-cholesterol; triglycerides; phospholipids; fatty acid composition), plasma protein status (total protein, albumin, transthyretin, orosomucoid, CRP, transferrin), antioxidant capacity (plasma selenium, uric acid, retinol, alpha-tocopherol and tocotrienols levels, plasma seleno-glutathione peroxidase (GSHPx) activity) and oxidative stress markers (malondialdehyde (MDA) and advanced oxidation protein products (AOPP)).

RESULTS:The mountain region samples (Glanle) were characterized by significantly lower plasma albumin, total-, HDL- and LDL-cholesterol, retinol and selenium levels, plasma PUFA content and GSHPx activity, but significantly higher alpha-tocopherol index and total tocotrienol level, than controls from the coastal area (Bodou). These results suggest a higher exposure risk to oxidative stress for the mountain region subjects. However, the absence of oxidative damage in this group provides evidence of a selenium independent protection mechanism against oxidative stress. This protection is related to lower plasma LDL cholesterol and PUFA content, and to higher alpha-tocopherol index, delta and total tocotrienols.

CONCLUSION:The long-term consumption of crude palm oil could be considered as an effective protective factor against oxidative stress.

Suppression of diethylnitrosamine and 2-acetylaminofluorene-induced hepatocarcinogenesis in rats by tocotrienol-rich fraction isolated from rice bran oil.

Iqbal J, Minhajuddin M, Beg ZH.

Eur J Cancer Prev. 2004 Dec;13(6):515-20.

The anticancer efficacy of tocotrienol-rich fraction (TRF) was evaluated during diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)-induced hepatocarcinogenesis in male Sprague-Dawley rats. TRF treatment was carried out for 6 months, and was started 2 weeks before initiation phase of hepatocarcinogenesis. Morphological examination of the livers from DEN/AAF rats showed numerous off-white patches and few small nodules, which were significantly reduced by TRF treatment. Cytotoxic damage by DEN/AAF was estimated by alkaline phosphatase (ALP) release into the plasma from the cell membranes. DEN/AAF caused a twofold increase in the activity of ALP in plasma as compared with normal control rats, and this increase was prevented significantly by TRF treatment. We observed an increase of 79% in liver ALP activity in DEN/AAF rats, which was further increased by another 48% after the administration of TRF. Hepatic activity of glutathione S-transferase (GST) was also increased (3.5-fold) during the induction of hepatic carcinogenesis. Lipid peroxidation and low-density lipoprotein (LDL) oxidation increased threefold following initiation by DEN/AAF as compared with normal control rats. However, TRF treatment to DEN/AAF-treated rats substantially decreased (62-66%) the above parameters and thus limited the action of DEN/AAF. We conclude that long-term intake of TRF could reduce cancer risk by preventing hepatic lipid peroxidation and protein oxidation damage due to its antioxidant actions.

Vitamin E and breast cancer

Kline K, Yu W, Sanders BG.

J Nutr. 2004 Dec;134(12 Suppl):3458S-3462S.

Vitamin E is a term that describes a group of compounds with similar yet unique chemical structures and biological activities. One interesting property possessed by certain vitamin E compounds-namely, delta-tocotrienol, RRR-alpha-tocopheryl succinate [vitamin E succinate (VES), a hydrolyzable ester-linked succinic acid analogue of RRR-alpha-tocopherol], and a novel vitamin E analogue referred to as alpha-TEA (alpha-tocopherol ether linked acetic acid analogue, which is a stable nonhydrolyzable analogue of RRR-alpha-tocopherol)-is their ability to induce cancer cells but not normal cells to undergo a form of cell death called apoptosis. In contrast, the parent compound, RRR-alpha-tocopherol, also referred to as natural or authentic vitamin E and known for its antioxidant properties, does not induce cancer-cell apoptosis. Efforts to understand how select vitamin E forms can induce cancer cells to undergo apoptosis have identified several nonantioxidant biological functions, including restoration of pro-death transforming growth factor-beta and Fas signaling pathways. Recent studies with alpha-TEA show it to be a potent inducer of apoptosis in a wide variety of epithelial cancer cell types, including breast, prostate, lung, colon, ovarian, cervical, and endometrial in cell culture, and to be effective in significantly reducing tumor burden and metastasis in a syngeneic mouse mammary tumor model, as well as xenografts of human breast cancer cells. Studies also show that alpha-TEA, in combination with the cyclooxygenase-2 inhibitor celecoxib and the chemotherapeutic drug 9-nitro-camptothecin decreases breast cancer animal model tumor burden and inhibits metastasis significantly better than do single-agent treatments.

Vitamin E: Underestimated as an antioxidant

Pfluger P, Kluth D, Landes N, Bumke-Vogt C, Brigelius-Flohé R.

Redox Rep. 2004;9(5):249-54.

Some 80 years after its discovery, vitamin E has experienced a renaissance which is as surprising as it is trivial. Although vitamin E is essential for reproduction, in rats at least, and deficiency causes neurological disorders in humans, the main interest in the last decades has concentrated on its antioxidant functions. This focus has highly underestimated the biological importance of vitamin E, which by far exceeds the need for acting as a radical scavenger. Only recently has it become clear that vitamin E can regulate cellular signaling and gene expression. Out of the eight different tocols included in the term vitamin E, alpha-tocopherol often exerts specific functions, which is also reflected in its selective recognition by proteins such as the alpha-tocopherol transfer protein and alpha-tocopherol-associated proteins. Vitamin E forms other than alpha-tocopherol are very actively metabolised, which explains their low biopotency. In vivo, metabolism may also attenuate the novel functions of gamma-tocopherol and tocotrienolsobserved in vitro. On the other hand, metabolites derived from individual forms of vitamin E have been shown to exert effects by themselves. This article focuses on the metabolism and novel functions of vitamin E with special emphasis on differential biological activities of individual vitamin E forms.

Tocotrienol: The natural vitamin E to defend the nervous system?

Sen CK, Khanna S, Roy S.

Ann N Y Acad Sci. 2004 Dec;1031:127-42.

Vitamin E is essential for normal neurological function. It is the major lipid-soluble, chain-breaking antioxidant in the body, protecting the integrity of membranes by inhibiting lipid peroxidation. Mostly on the basis of symptoms of primary vitamin E deficiency, it has been demonstrated that vitamin E has a central role in maintaining neurological structure and function. Orally supplemented vitamin E reaches the cerebrospinal fluid and brain. Vitamin E is a generic term for all tocopherols and their derivatives having the biological activity of RRR-alpha-tocopherol, the naturally occurring stereoisomer compounds with vitamin E activity. In nature, eight substances have been found to have vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. Often, the term vitamin E is synonymously used with alpha-tocopherol. Tocotrienols, formerly known as zeta, , or eta-tocopherols, are similar to tocopherols except that they have an isoprenoid tail with three unsaturation points instead of a saturated phytyl tail. Although tocopherols are predominantly found in corn, soybean, and olive oils, tocotrienols are particularly rich in palm, rice bran, and barley oils. Tocotrienols possess powerful antioxidant, anticancer, and cholesterol-lowering properties. Recently, we have observed that alpha-tocotrienol is multi-fold more potent than alpha-tocopherol in protecting HT4 and primary neuronal cells against toxicity induced by glutamate as well as by a number of other toxins. At nanomolar concentration, tocotrienol, but not tocopherol, completely protected neurons by an antioxidant-independent mechanism. Our current work identifies two major targets of tocotrienol in the neuron: c-Src kinase and 12-lipoxygenase. Dietary supplementation studies have established that tocotrienol, fed orally, does reach the brain. The current findings point towards tocotrienol as a potent neuroprotective form of natural vitamin E.

Tocotrienol-rich fraction from palm oil and gene expression in human breast cancer cells

Nesaretnam K, Ambra R, Selvaduray KR, Radhakrishnan A, Canali R, Virgili F.

Ann N Y Acad Sci. 2004 Dec;1031:143-57.

Vitamin E is important not only for its cellular antioxidant and lipid-lowering properties, but also as an antiproliferating agent. It has also been shown to contribute to immunoregulation, antibody production, and resistance to implanted tumors. It has recently been shown that tocotrienols are the components of vitamin E responsible for growth inhibition in human breast cancer cells in vitro as well as in vivo through estrogen-independent mechanisms. Although tocotrienols act on cell proliferation in a dose-dependent manner and can induce programmed cell death, no specific gene regulation has yet been identified. In order to investigate the molecular basis of the effect of a tocotrienol-rich fraction (TRF) from palm oil, we performed a cDNA array analysis of cancer-related gene expression in estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells. The human breast cancer cells were incubated with or without 8 mug/mL of tocotrienols for 72 h. RNA was subsequently extracted and subjected to reverse transcription before being hybridized onto cancer arrays. Tocotrienol supplementation modulated significantly 46 out of 1200 genes in MDA-MB-231 cells. In MCF-7 cells, tocotrienol administration was associated with a lower number of affected genes. Interestingly, only three were affected in a similar fashion in both cell lines: c-myc binding protein MM-1, 23-kDa highly basic protein, and interferon-inducible protein 9-27 (IFITM-1). These proteins are most likely involved in the cell cycle and can exert inhibitory effects on cell growth and differentiation of the tumor cell lines. These data suggest that tocotrienols are able to affect cell homeostasis, possibly independent of their antioxidant activity.

Gamma-tocotrienol metabolism and antiproliferative effect in prostate cancer cells

Conte C, Floridi A, Aisa C, Piroddi M, Floridi A, Galli F.

Ann N Y Acad Sci. 2004 Dec;1031:391-4.

In this study, we evaluated the antiproliferative effect of tocotrienols (T3) and the presence of a specific vitamin E metabolism in PC3 and LNCaP prostate cancer cells. These cell lines are able to transform tocopherols (T) and T3 in the corresponding carboxyethyl-hydroxychromans metabolites (CEHCs). The extent of this metabolism and the inhibitory effect on cell growth followed the order of magnitude alpha-T<alpha-T3<gamma-T<gamma-T3. The partial inhibition of gamma-T3 metabolism by ketoconazole did not influence cell proliferation. These early findings may suggest that the transformation of vitamin E to CEHC is mostly a detoxification mechanism useful to maintain the malignant properties of prostate cancer cells.

Antiangiogenic potency of vitamin E

Miyazawa T, Tsuzuki T, Nakagawa K, Igarashi M.

Ann N Y Acad Sci. 2004 Dec;1031:401-4.

We investigated the antiangiogenic property and mechanism of vitamin E compounds, with particular emphasis on tocotrienol (T3), a natural analogue of tocopherol (Toc). T3 inhibited both the proliferation and tube formation of bovine aortic endothelial cells, with delta-T3 appearing to have the highest activity. delta-T3 also reduced the vascular endothelial growth factor (VEGF)-stimulated tube formation by human umbilical vein endothelial cells. Moreover, delta-T3 inhibited the new blood vessel formation on the growing chick embryo chorioallantoic membrane (assay for in vivo angiogenesis). Orally administered T3 suppressed the tumor cell-induced angiogenesis in the mouse dorsal air sac assay. In contrast with T3, Toc showed very weak inhibition. Based on DNA microarray analysis, antiangiogenic effect of T3 was attributable in part to regulation of intracellular VEGF signaling (phospholipase C-gamma and protein kinase C). Our findings suggest that T3 has potential as a therapeutic dietary supplement for preventing angiogenic disorders.

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