Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered apoptosis.
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Fas (CD95/APO-1) is an important mediator of apoptosis. We show that Fas-resistant MCF-7, MDA-MB-231, and MDA-MB-435 human breast cancer cells become responsive to anti-Fas (CD95) agonistic antibody-triggered apoptosis after pretreatment or cotreatment with vitamin E succinate (VES; RRR-alpha-tocopheryl succinate). In contrast, no enhancement of anti-Fas agonistic antibody-triggered apoptosis was observed following VES pretreatment or cotreatment with Fas-sensitive primary cultures of human mammary epithelial cells, immortalized MCF-10A cells, or T47D human breast cancer cells. Although VES is itself a potent apoptotic triggering agent, the 6-h pretreatment procedure for Fas sensitization did not initiate VES-mediated apoptosis. The combination of VES plus anti-Fas in pretreatment protocols was synergistic, inducing 2.8-, 3.0-, and 6.3-fold enhanced apoptosis in Fas-resistant MCF-7, MDA-MB-231, and MDA-MB-435 cells, respectively. Likewise, cotreatment of Fas-resistant MCF-7, MDA-MB-231, and MDA-MB-435 cells with VES plus anti-Fas enhanced apoptosis 1.9-, 2.0-, and 2.6-fold, respectively. Functional knockout of Fas-mediated signaling with either Fas-neutralizing antibody (MCF-7-, MDA-MB-231-, and MDA-MB-435-treated cells) or Fas antisense oligomers (MDA-MB-435-treated cells only), reduced VES-triggered apoptosis by approximately 50%. Analyses of whole cell extracts from Fas-sensitive cells revealed high constitutive expression of Mr 43,000 Fas, whereas Fas-resistant cells expressed low levels that were confined to the cytosolic fraction. VES treatment of the Fas-resistant cells caused a depletion of cytosolic Mr 43,000 Fas with a concomitant increase in Mr 43,000 membrane Fas. These data show that VES can convert Fas-resistant human breast cancer cells to a Fas-sensitive phenotype, perhaps by translocation of cytosolic Mr 43,000 Fas to the membrane and show that VES-mediated apoptosis involves Mr 43,000 Fas signaling. (+info)
alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation.
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Alpha-Tocopheryl succinate (alpha-TOS), but not a-tocopherol, triggered apoptosis in Jurkat T cells. Apoptosis was induced by alpha-TOS in a time- and concentration-dependent mode, and signs of apoptosis were visible at concentrations of alpha-TOS as low as 30 microM, and within 3-5 h after addition of the ester. Employing a specific fluorogenic substrate, caspase-3 was found to be activated rapidly in response to alpha-TOS at 50 microM. We also found that Jurkat T cells challenged with alpha-TOS, when exposed to the lysosomotropic weak base acridine orange, showed decreased lysosomal uptake of the dye. This is suggestive of the involvement of lysosomal destabilisation in apoptosis of the cells. Apoptosis of Jurkat T cells induced with alpha-TOS also involved a drop in the mitochondrial membrane potential, although this phenomenon occurred after the initiation of lysosomal rupture. All apoptotic features observed with alpha-TOS were very similar to those found when cross-linking of the Fas receptor triggered apoptosis. These findings are consistent with the recent idea that vitamin E can contribute to elimination of malignant cells by the induction of apoptosis, and can be of (patho)physiological significance. (+info)
All-rac-alpha-tocopherol acetate is a better vitamin E source than all-rac-alpha-tocopherol succinate for broilers.
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The difference in bioavailabilities of the acetate and succinate esters of all-rac-alpha-tocopherol was investigated in a feeding experiment with broilers. The experiment was initiated with 96 12-d-old male Cobb broilers and lasted for 4 wk. The two sources of vitamin E were fed to eight groups of broilers at four different dietary levels (50, 100, 150 and 200 mg/kg feed, including the naturally occurring alpha-tocopherol). A total collection of droppings for determination of apparent tocopherol absorption were performed at two separate time periods (d 28-34 and d 35-41). There were no differences among the eight experimental groups with respect to animal performance or feed intake. At all dietary levels, the apparent absorption coefficient for all-rac-alpha-tocopherol succinate was significantly lower than that of the acetate ester. The mean (+/- SD) apparent absorption coefficient for all-rac-alpha-tocopherol succinate was 58.0 +/- 5.4 compared with 70. 8 +/- 5.6 for all-rac-alpha-tocopherol acetate. Furthermore, the apparent absorption coefficients for both esters was significantly lower in the first collection period (d 28-34) than in the second collection period (d 35-41). This difference in the apparent absorption coefficient between the succinate and the acetate ester was accompanied by significant differences in alpha-tocopherol concentrations in plasma, breast muscle, liver and adipose tissue of the broilers, which were lower in those fed the succinate ester. Based on a comparison of plasma and tissue responses, the succinate ester was utilized only 69-76% as efficiently as the acetate ester. In vitro studies showed a significantly higher capacity of pancreatic carboxyl ester hydrolase to hydrolyze alpha-tocopherol acetate compared to alpha-tocopherol succinate. This difference in intestinal hydrolysis of the two vitamin E sources may explain the observed differences in biopotency. (+info)
Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model.
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We have previously shown that chronic activation of mitogenic signaling induced by over-expression of c-myc and transforming growth factor-alpha (TGFalpha) transgenes in mouse liver induces a state of oxidative stress. We therefore proposed that increased reactive oxygen species (ROS) generation might be responsible for the extensive chromosomal damage and acceleration of hepatocarcinogenesis characteristic for TGFalpha/c-myc mice. In this study, we show that vitamin E (VE), a potent free radical scavenging antioxidant, is able to protect liver tissue against oxidative stress and suppress tumorigenic potential of c-myc oncogene. Dietary supplementation with VE, starting from weaning, decreased ROS generation coincident with a marked inhibition of hepatocyte proliferation while increasing the chromosomal as well as mtDNA stability in the liver. Similarly, dietary VE reduced liver dysplasia and increased viability of hepatocytes. At 6 mo of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by over-expression of c-myc and TGFalpha in the liver are the primary carcinogenic agents in this animal model. Furthermore, the data demonstrate that dietary supplementation of VE can effectively inhibit liver cancer development. (+info)
Lipoprotein-associated alpha-tocopheryl-succinate inhibits cell growth and induces apoptosis in human MCF-7 and HBL-100 breast cancer cells.
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alpha-Tocopheryl succinate (alpha-TS) is a potent inhibitor of tumor cell proliferation. The goal of the present study was to investigate whether and to what extent alpha-TS associates with plasma lipoproteins and if alpha-TS-enriched lipoproteins inhibit breast cancer cell growth in a manner comparable to the free drug. In vitro enrichment of human plasma revealed that alpha-TS readily associated with the main lipoprotein classes, findings confirmed in vivo in mice. At the highest alpha-TS concentrations, lipoproteins carrying 50000 (VLDL), 5000 (LDL) and 700 (HDL) alpha-TS molecules per lipoprotein particle were generated. alpha-TS enrichment generated lipoprotein particles with slightly decreased density and increased particle radius. To study whether the level of LDL-receptor (LDL-R) expression affects alpha-TS uptake from apoB/E containing lipoprotein particles human breast cancer cells with low (MCF-7) and normal (HBL-100) LDL-R expression were used. The uptake of free, VLDL- and (apoE-free) HDL(3)-associated alpha-TS was nearly identical for both cell lines. In contrast, uptake of LDL-associated alpha-TS by HBL-100 cells (normal LDL-R expression) was about twice as high as compared to MCF-7 cells (low LDL-R expression). VLDL and LDL-associated alpha-TS inhibited proliferation most effectively at the highest concentration of alpha-TS used (100% inhibition of MCF-7 growth with 20 microg/ml of lipoprotein-associated alpha-TS). However, also alpha-TS-free VLDL and LDL inhibited HBL-100 cell proliferation up to 55%. In both cell lines, alpha-TS-enriched HDL(3) inhibited cell growth by 40-60%. Incubation of both cell lines in the presence of free or lipoprotein-associated alpha-TS resulted in DNA fragmentation indicative of apoptosis. Collectively, the present findings demonstrate that: (1) alpha-TS readily associates with lipoproteins in vitro and in vivo; (2) the lipoprotein-enrichment efficacy was dependent on the particle size and/or the triglyceride content of the lipoprotein; (3) uptake of LDL-associated alpha-TS was apparently dependent on the level of LDL-R expression; and (4) lipoproteins were efficient alpha-TS carriers inducing reduced cell proliferation rates and apoptosis in human breast cancer cells as observed for the free drug. (+info)
Effects of vitamin E and selenium supplementation on esophageal adenocarcinogenesis in a surgical model with rats.
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Two well-known antioxidative nutrients, vitamin E and selenium, were used in this study to investigate possible inhibitory action against the formation of esophageal adenocarcinoma (EAC) in rats. In this model, carcinogenesis is believed to be driven by oxidative stress. Male Sprague-Dawley rats (8 weeks old) were divided into four groups and received esophagoduodenal anastomosis (EDA) surgery plus iron supplementation (12 mg/kg/week). Vitamin E and selenium were supplemented in the diet in the forms of alpha-tocopheryl acetate (750 IU/kg) and sodium selenate (1.7 mg Se/kg), which were 10 times the regular amounts in the basic AIN93M diet. At 40 weeks after surgery, all the EDA groups had lower body weights than the non-operated control group. Iron nutrition (hemoglobin, total serum iron and transferrin saturation) was normal as a result of iron supplementation after EDA. Vitamin E supplementation maintained the normal plasma level of alpha-tocopherol in EDA rats, but not those of gamma-tocopherol and retinol. Selenium supplementation increased the serum and liver selenium contents of the EDA rats. Histopathological analysis showed that selenium supplementation increased the incidence of EAC and the tumor volume. The selenium level in the tumor is higher than that in the duodenum of the same animal. Vitamin E supplementation, however, inhibited carcinogenesis, especially in the selenium-supplemented group. We believe that vitamin E exerts its effect through its antioxidative properties, and a high dose of inorganic selenium may promote carcinogenesis by enhancing oxidative stress. (+info)
Oxidation of plasma proteins is not increased after supplementation with eicosapentaenoic and docosahexaenoic acids.
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BACKGROUND: It is generally thought that as the intake of dietary polyunsaturated fatty acids increases, so should that of alpha-tocopherol, to protect the polyunsaturated fatty acids from increased in vivo peroxidation. However, there are little quantitative data about the concentration of alpha-tocopherol that is necessary when eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are consumed. OBJECTIVE: The purpose of this study was to measure changes produced in 2 indexes of lipid oxidation after supplementation with EPA and DHA from fish oil and 3 doses of RRR-alpha-tocopheryl acetate in postmenopausal women. DESIGN: Daily supplements of fish oil providing 2.5 g EPA and 1.8 g DHA and 0, 100, 200, or 400 mg alpha-tocopheryl acetate were given to 46 postmenopausal women in a 4-treatment, 4-period crossover design. RESULTS: The supplements increased plasma concentrations of EPA, DHA, and alpha-tocopherol. The fish-oil supplement increased the plasma concentration of thiobarbituric acid-reactive substances (TBARS) (P: = 0.0001) but not that of oxidatively modified protein, as indicated by the carbonyl content. The alpha-tocopheryl acetate and fish-oil supplements had no significant effect on plasma concentrations of TBARS or oxidized protein. CONCLUSIONS: Although these data show a small but statistically significant increase in oxidative stress on the basis of plasma TBARS concentrations after the consumption of EPA and DHA, the clinical relevance of this change is questionable. In addition, as supplements of alpha-tocopheryl acetate were added to the diet, neither the plasma TBARS concentration nor the protein oxidation changed. Consequently, the results of this study indicate that there is no basis for vitamin E supplementation after consumption of EPA and DHA. (+info)
Selective cancer cell killing by alpha-tocopheryl succinate.
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We report that alpha-tocopheryl succinate, a vitamin E analogue with pro-apoptotic properties, selectively kills cells with a malignant or transformed phenotype, i.e. multiple haematopoietic and carcinoma cell lines, while being non-toxic to normal, i.e. primary and non-transformed cells. These findings strongly suggest a potential of this micronutrient in the therapy and/or prevention of cancer without significant side-effects. (+info)