Vitamin E compounds exhibit prostate cancer preventive properties experimentally, but serologic investigations of tocopherols, and randomized controlled trials of supplementation in particular, have been inconsistent. Many studies suggest protective effects among smokers and for aggressive prostate cancer, however.
We conducted a nested case-control study of serum α-tocopherol and γ-tocopherol and prostate cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, with 680 prostate cancer cases and 824 frequency-matched controls. Multivariate-adjusted, conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for tocopherol quintiles.
Serum α-tocopherol and γ-tocopherol were inversely correlated (r = −0.24, p<0.0001). Higher serum α-tocopherol was associated with significantly lower prostate cancer risk (OR for the highest vs. lowest quintile = 0.63, 95% CI 0.44–0.92, p-trend 0.05). By contrast, risk was non-significantly elevated among men with higher γ-tocopherol concentrations (OR for the highest vs. lowest quintile = 1.35, 95% CI 0.92–1.97, p-trend 0.41). The inverse association between prostate cancer and α-tocopherol was restricted to current and recently former smokers, but was only slightly stronger for aggressive disease. By contrast, the increased risk for higher γ-tocopherol was more pronounced for less aggressive cancers.
Our findings indicate higher α-tocopherol status is associated with decreased risk of developing prostate cancer, particularly among smokers. Although two recent controlled trials did not substantiate an earlier finding of lower prostate cancer incidence and mortality in response to supplementation with a relatively low dose of α-tocopherol, higher α-tocopherol status may be beneficial with respect to prostate cancer risk among smokers. Determining what stage of prostate cancer development is impacted by vitamin E, the underlying mechanisms, and how smoking modifies the association, is needed for a more complete understanding of the vitamin E-prostate cancer relation.
In contrast to strong epidemiologic, preclinical, and secondary clinical evidence for vitamin E (tocopherols) in reducing cancer risk, large-scale clinical cancer-prevention trials of α-tocopherol have been negative. This vexing contrast helped spur substantial preclinical efforts to better understand and improve the antineoplastic activity of tocopherol through, for example, the study of different tocopherol forms. We previously showed that the γ-tocopherol–rich mixture (γ-TmT) effectively inhibited colon and lung carcinogenesis and the growth of transplanted lung-cancer cells in mice. We designed the present study to determine the relative activities of different forms of tocopherol in a xenograft model, comparing the anticancer activities of δ-tocopherol with those of α- and γ-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received α-, γ-, or δ-tocopherol or γ-TmT in the diet (each at 0.17% and 0.3%) for 49 days. δ-Tocopherol inhibited tumor growth most strongly. γ-Tocopherol and γ-TmT (at 0.3%) also inhibited growth significantly, but α-tocopherol did not. δ-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, γ-tocopherol also was active in these regards but less so, and α-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol—up to 45 µM for α-tocopherol, 9.7 µM for γ-tocopherol, and 1.2 µM for δ-tocopherol; dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol. Each dietary tocopherol also increased its corresponding side-chain–degradation metabolites, with concentrations of δ-tocopherol metabolites greater than γ-tocopherol and far greater than α-tocopherol metabolites in serum and tumors. The present study is the first in vivo assessment of δ-tocopherol in tumorigenesis and demonstrates that δ-tocopherol is more active than α- or γ-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; δ-tocopherol metabolites could contribute significantly to these results.
Tocopherols; lung cancer cells; xenograft; tocopherol metabolites
We investigated the association of dietary α-tocopherol, γ-tocopherol, and supplemental vitamin E intake with the risk of esophageal squamous cell carcinoma (ESCC; n = 158), esophageal adenocarcinoma (EAC; n = 382), gastric cardia adenocarcinoma (GCA; n = 320), and gastric noncardia adenocarcinoma (GNCA; n = 327) in the NIH-AARP Diet and Health Study, a cohort of approximately 500,000 people. Data on dietary and supplemental vitamin E intake were collected using a validated questionnaire at baseline and were analyzed using Cox regression models. Intakes were analyzed as continuous variables and as quartiles.
For dietary α-tocopherol, we found some evidence of association with decreased ESCC and increased EAC risk in the continuous analyses, with adjusted hazard ratios (HR) and 95% confidence intervals (CI) of 0.90 (0.81 – 0.99) and 1.05 (1.00 – 1.11), respectively, per 1.17 mg (half the interquartile range) increased intake. However, in quartile analyses, the p-value for trend was non-significant for both of these cancers. There was no association between dietary α-tocopherol and GCA or GNCA. We observed no statistically significant associations with γ-tocopherol. For supplemental vitamin E, the results were mainly null, except for a significantly lower risk of GNCA with higher doses of supplemental vitamin E. An increase of 71 mg/day (half the interquartile range) in supplemental vitamin E had an HR (95% CI) of 0.92 (0.85–1.00) and the p-value for trend in the quartile analyses was 0.015.
Alpha-Tocopherol and gamma-tocopherol are the two major forms of vitamin E in human plasma and the primary lipid soluble antioxidants. The dietary intake of gamma-tocopherol is generally higher than that of alpha-tocopherol. However, alpha-tocopherol plasma levels are about four fold higher than those of gamma-tocopherol. Among other factors, a preferential cellular uptake of gamma-tocopherol over alpha-tocopherol could contribute to the observed higher plasma alpha-tocopherol levels. In this investigation, we studied the uptake and depletion of both alpha-tocopherol and gamma-tocopherol (separately and together) in cultured RAW 264.7 macrophages. Similar studies were performed with alpha-tocopheryl quinone and gamma-tocopheryl quinone, which are oxidation products of tocopherols.
RAW 264.7 macrophages showed a greater uptake of gamma-tocopherol compared to alpha-tocopherol (with uptake being defined as the net difference between tocopherol transported into the cells and loss due to catabolism and/or in vitro oxidation). Surprisingly, we also found that the presence of gamma-tocopherol promoted the cellular uptake of alpha-tocopherol. Mass balance considerations suggest that products other than quinone were formed during the incubation of tocopherols with macrophages.
Our data suggests that gamma-tocopherol could play a significant role in modulating intracellular antioxidant defence mechanisms. Moreover, we found the presence of gamma-tocopherol dramatically influenced the cellular accumulation of alpha-tocopherol, i.e., gamma-tocopherol promoted the accumulation of alpha-tocopherol. If these results could be extrapolated to in vivo conditions they suggest that gamma-tocopherol is selectively taken up by cells and removed from plasma more rapidly than alpha-tocopherol. This could, in part, contribute to the selective maintenance of alpha-tocopherol in plasma compared to gamma-tocopherol.
Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of γ-tocopherol is higher than α-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used α-tocopherol. Recent epidemiological, experimental and molecular studies suggest that γ-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied α-tocopherol. γ-Tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor γ (PPARγ) is a promising molecular target for colon cancer prevention. Upregulation of PPARγ activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARγ ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both α and γ tocopherol on the expression of PPARγ mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines.
We have discovered that the α and γ isoforms of vitamin E upregulate PPARγ mRNA and protein expression in the SW480 colon cancer cell lines. γ-Tocopherol is a better modulator of PPARγ expression than α-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, γ-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of α-tocopherol.
Our data suggest that both α and γ tocopherol can upregulate the expression of PPARγ which is considered an important molecular target for colon cancer chemoprevention. We show that the expression of PPARγ mRNA and protein are increased and these effects are more pronounced with γ-tocopherol. γ-Tocopherol's ability to upregulate PPARγ expression and achieve higher intracellular concentrations in the colonic tissue may be relevant to colon cancer prevention. We also show that the intracellular concentrations of γ-tocopherol are several fold higher than α-tocopherol. Further work on other colon cancer cell lines are required to quantitate differences in the ability of these forms of vitamin E to induce apoptosis, suppress cell proliferation and act as PPAR ligands as well as determine their effects in conjunction with other chemopreventive agents. Upregulation of PPARγ by the tocopherols and in particular by γ-tocopherol may have relevance not only to cancer prevention but also to the management of inflammatory and cardiovascular disorders.
d-α-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-α-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-α-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice were killed at either 2 or 6 weeks after the start of dietary intervention. During necropsy, tumor and host tissues were excised for histology and for biochemical analyses.
Tumor growth was significantly reduced by 6 weeks of sE supplementation. Thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were suppressed in tumor and in host tissues in sE supplemented mice. In the sE treated mice, the fatty acid composition of microsomal and mitochondrial membranes of tumor and host tissues had proportionately less linoleic acid (n-6 C 18-2), similar levels of arachidonic acid (n-6 C 20-4), but more docosahexanoic acid (n-3 C 22-6). The sE supplementation had no significant effect on blood counts or on intestinal histology but gave some evidence of cardiac toxicity as judged by myocyte vacuoles and by an indicator of oxidative stress (increased ratio of Mn SOD mRNA over GPX1 mRNA).
At least one of the stereoisomers in sE has antitumor activity. Synthetic vitamin E appears to preferentially stabilize membrane fatty acids with more double bonds in the acyl chain. Although sE suppressed tumor growth and lipid peroxidation, it may have side-effects in the heart.
Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of 4 isoforms, α, β, γ, and δ variants, and recent attention is being made to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis.
Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells.
Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3 and peroxisome proliferator activated receptor-γ (PPAR-γ), and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated PPAR-γ and antagonized estrogen action in breast cancer.
The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer.
breast cancer; γ-tocopherol; δ-tocopherol; estrogen receptor; PPAR-γ
Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ- or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). While administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (p<0.01) and 7.1 ± 0.7 g (p<0.01), respectively. Tumor multiplicity was also reduced in δ- and γ-tocopherol treatment groups by 42% (p<0.001) and 32% (p<0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of pro-apoptotic markers (BAX, cleaved-caspase 9, cleaved-caspase 3, cleaved-PARP) were increased, while anti-apoptotic markers (Bcl2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKC α), survival (PPARγ, PTEN, phospho-Akt) and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, appear to be promising agents for the prevention of hormone-dependent breast cancer.
Breast Cancer; Tocopherols; Apoptosis; Cell Cycle; PPARγ
Fish, vitamin D, flavonoids, and flavonoid-containing foods may have cardiovascular benefits and therefore may also reduce the risk of renal cell cancer. Risk was prospectively assessed in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (1985–2002) cohort (N = 27,111; 15.2 mean person-years of follow-up). At enrollment, demographic, health, and dietary history information was recorded. Individuals who smoked less than 5 cigarettes/day, with chronic renal insufficiency or prior cancer, were excluded. Hazard ratios and 95% confidence intervals from Cox regression were used to compare upper quartiles (quartiles 2–4) with the lowest quartile (quartile 1) of dietary intake. Among 228 cases, risk (quartile 4 vs. quartile 1) was associated with consumption of the flavonoid quercetin (hazard ratio = 0.6, 95% confidence interval: 0.4, 0.9; Ptrend = 0.015) and Baltic herring (hazard ratio = 2.0, 95% confidence interval: 1.4, 3.0; Ptrend < 0.001), with adjustment for age, body mass index, smoking, blood pressure, alcohol use, physical activity, urban residence, and education. In geographically stratified models, the risks associated with herring and total fish intake appeared to be highest in the urban coast region, although the interaction was not statistically significant. These results suggest that the flavonoid quercetin may prevent renal cell cancer among male smokers. The possible risk associated with fish intake warrants further investigation before conclusions may be drawn.
carcinoma (renal cell); fish products; flavonoids; vitamin D
While smoking is the primary risk factor for lung cancer, there is evidence to suggest that fruit and vegetable intake are important co-factors. The present case-control study, nested within the Multiethnic Cohort Study, examined the associations of biomarkers of fruit and vegetable intake (individual plasma micronutrient levels), serum selenium and a urinary biomarker for total lipid peroxidation with lung cancer risk. 207 incident cases were matched to 414 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection and hours of fasting. We measured prediagnositic circulating levels of individual tocopherols and carotenoids, retinol, and serum selenium, and urinary 15-isoprostane F2t. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). For men, strong reductions in risk were seen with increasing tertiles of each plasma carotenoid, with the ORs for the third tertile, compared to the first tertile, ranging from 0.24 to 0.45 (p for trends: 0.002-0.04). No associations were found among women for carotenoids or among either sex for tocopherols, selenium and retinol. A doubling in risk was seen for men in the second and third tertiles, compared to the first tertile of urinary 15-isoprostane F2t (OR=2.31, 95% CI: 1.02-5.25 and OR=2.16, 95% CI: 0.98-4.78). This study supports the previously observed association between circulating carotenoids and lung cancer risk in men, and adds to the limited literature regarding urinary 15-isoprostane F2t as a marker of cancer risk. Future research examining the possible relationship between isoprostanes and lung cancer is warranted.
antioxidant; biomarkers; tocopherol; carotenoid; selenium; retinol; isoprostane; lipid peroxidation; lung cancer
A role for vitamin D in cancer risk reduction has been hypothesized, but few data exist for lung cancer. We investigated the relationship between vitamin D status, using circulating 25-hydroxyvitamin D [25(OH)D], and lung cancer risk in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers.
Lung cancer cases (n = 500) were randomly selected based on month of blood collection, and 500 controls were matched to them based on age and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariate-adjusted conditional logistic regression. To account for seasonal variation in 25(OH)D concentrations, season-specific and season-standardized quintiles of 25(OH)D were examined, and models were also stratified on season of blood collection (darker season = November–April and sunnier season = May–October). Pre-determined, clinically-defined cutpoints for 25(OH)D and 25(OH)D as a continuous measure were also examined.
Overall, 25(OH)D was not associated with lung cancer. Risks were 1.08 (95% CI 0.67–1.75) and 0.83 (95% CI 0.53–1.31) in the highest vs. lowest season-specific and season-standardized quintiles of 25(OH)D, respectively, and 0.91 (95% CI 0.48–1.72) for the ≥75 vs. <25 nmol/L clinical categories. Inverse associations were, however, suggested for subjects with blood collections from November–April, with ORs of 0.77 (95% CI 0.41–1.45, p-trend = 0.05) and 0.65 (95% CI 0.37–1.14, p-trend = 0.07) in the highest vs. lowest season-specific and season-standardized quintiles of 25(OH)D, respectively, and 0.61 (95% CI 0.24–1.52, p-trend = 0.01) for ≥75 vs. <25 nmol/L. We also found 11% lower risk for a 10 nmol/L increase in 25(OH)D in the darker season based on the continuous measure (OR = 0.89, 95% CI 0.81–0.98, p = 0.02).
In this prospective study of male smokers, circulating 25(OH)D was not associated with lung cancer risk overall, although inverse associations were suggested among those whose blood was drawn during darker months.
Tocopherols, which exist in α, β, γ, and δ forms, are antioxidative nutrients also known as vitamin E. Although α-tocopherol (α-T) is the major form of vitamin E found in the blood and tissues, γ- and δ-T have been suggested to have stronger anti-inflammatory activities. In the present study, using a tocopherol mixture that is rich in γ-T (γ-TmT, which contains 57% γ-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, γ-TmT inhibited chemically-induced lung tumorigenesis in the A/J mice as well as the growth of human lung cancer cell H1299 xenograft tumors. γ-TmT also decreased the levels of 8-hydroxydeoxyguanosine, γ-H2AX, and nitrotyrosine in tumors. More evident anti-inflammatory and cancer preventive activities of dietary γ-TmT were demonstrated in mice treated with azoxymethane and dextran sulfate sodium. These results demonstrate the anti-oxidative, anti-inflammatory, and anti-carcinogenic activities of tocopherols.
Tocopherols; Antioxidant; Anti-inflammation; Anti-Carcinogenesis; Lung; Colon
Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The Oxygen Radical Absorbance Capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements, and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) were inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
The oxidative metabolism of tocopherols and tocotrienols by monooxygenases is a key factor in the plasma and tissue clearance of forms of vitamin E other than α-tocopherol. It is well known that a commonly ingested form of vitamin E, γ-tocopherol, has greatly reduced plasma half life (faster clearance) than α-tocopherol. The tocotrienols are metabolized even faster than γ-tocopherol. Both γ-tocopherol and α- and δ-tocotrienol possess intriguing biological activities that are different from α-tocopherol, making them potentially of interest for therapeutic use. Unfortunately, the fast clearance of non-α-tocopherols from animal tissues is a significant hurdle to maximizing their effect(s) as dietary supplements. We report here the design and synthesis of N-heterocycle-containing analogues of α-tocopherol that act as inhibitors of Cyp4F2, the key monooxygenase responsible for ω-hydroxylation of the side chain of tocols. In particular, an ω-imidazole containing compound, 1, [(R)-2-(9-(1H-imidazol-1-yl)nonyl)-2,5,7,8-tetramethylchroman-6-ol] had an ED50 for inhibition of γ-CEHC production from γ-tocopherol of ~ 1 nM when tested in HepG2 cells in culture. Furthermore, feeding of 1 to mice along with rapidly metabolized δ-tocopherol, resulted in a doubling of the δ-tocopherol / α-tocopherol ratio in liver (P < 0.05). Thus, 1 may be a useful adjuvant to the therapeutic use of non-α-tocopherols.
tocopherol; tocotrienol; vitamin E; oxidative metabolism; CYP4F2; enzyme inhibition
Vitamin E consists of eight different variants: α-, β-, γ-, and δ-tocopherols (saturated phytyl tail) and α-, β-, γ-, and δ-tocotrienols (unsaturated phytyl tail). Cancer prevention studies with vitamin E have primarily utilized the variant α-tocopherol. To no avail, a majority of these studies focused on variant α-tocopherol with inconsistent results. However, γ-tocopherol, and more recently δ-tocopherol, have shown greater ability to reduce inflammation, cell proliferation, and tumor burden. Recent results have shown that γ-enriched mixed tocopherols inhibit the development of mammary hyperplasia and tumorigenesis in animal models. In this review, we discuss the possible differences between the variant forms, molecular targets, and cancer-preventive effects of tocopherols. We recommend that a γ-enriched mixture, γ- and δ-tocopherol, but not α-tocopherol, are promising agents for breast cancer prevention and warrant further investigation.
vitamin E; tocopherols; breast cancer; estrogen receptor (ER); peroxisome proliferator activated receptor γ (PPARγ); nuclear factor (erythroid-derived 2)-like 2 (Nrf2); anti-inflammatory; cell proliferation; apoptosis; case-control studies
Previous studies have found associations between one-carbon metabolism factors and risk of several cancers, but little is known regarding renal cell carcinoma (RCC). We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a prospective study of Finnish male smokers aged 50-69 at baseline.
Prediagnostic folate, vitamin B6, vitamin B12, cysteine, riboflavin and homocysteine concentrations were measured in fasting serum from 224 incident RCC cases and 224 controls (matched on age and date of serum collection). Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders.
Serum folate tended to be inversely associated with RCC; compared to the first quartile, the odds ratios (95% CI) for subsequent quartiles were 0.62 (0.35-1.08), 0.52 (0.29-0.93), and 0.67 (0.37-1.20) (P-trend = 0.19). When modeled as a threshold effect, subjects in the lowest serum folate quartile (≤ 6.64 nmol/L), which corresponds to deficient folate status, had a significant increased RCC risk (OR = 1.68, 95% CI 1.06-2.65) compared to those with higher serum folate. The other one-carbon metabolism biomarkers were not associated with RCC.
This study in male smokers suggests that deficient folate status may increase risk of RCC, but confirmation is needed in other epidemiologic studies that include women and non-smokers.
folate; renal cell carcinoma; biological markers; nested case-control study; B vitamins
Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. Clinical studies suggest a number of protective dietary factors for asthma, including vitamin E. However, studies of vitamin E in allergy commonly result in seemingly conflicting outcomes. Recent work indicates that allergic inflammation is inhibited by supplementation with the purified natural vitamin E isoform α-tocopherol but elevated by the isoform γ-tocopherol when administered at physiological tissue concentrations. In this review, we discuss opposing regulatory effects of α-tocopherol and γ-tocopherol on allergic lung inflammation in clinical trials and in animal studies. A better understanding of the differential regulation of inflammation by isoforms of vitamin E provides a basis towards the design of clinical studies and diets that would effectively modulate inflammatory pathways in lung disease.
tocopherols; lung disease; endothelial
Folate intake has been associated with reduced colorectal cancer risk; however, few studies have prospectively examined circulating folate or other related one-carbon biomarkers.
We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 50−69 year old Finnish men to investigate associations between serum folate, vitamin B6, vitamin B12, riboflavin, and homocysteine and risk of colon and rectal cancers. Controls were alive and cancer free at the time of case diagnosis and matched 1:1 on age and date of baseline fasting serum collection with cases (152 colon and 126 rectal cancers). Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.
Serum vitamin B6 was inversely associated with colon cancer (OR=0.30, 95% CI 0.11−0.82 in the highest vs. lowest quintile). An increased risk of colon cancer was suggested for men in the middle quintile of serum folate, but without indication of a dose-response relationship. None of the other serum biomarkers were associated with colon or rectal cancer, and we observed no interactions with alcohol consumption or methionine or protein intake. A priori combinations of the five one-carbon serum biomarkers provided no clear evidence to support a collective influence on colorectal cancer risk.
Our results support the hypothesis that higher vitamin B6 status may play a role in inhibiting colon cancer carcinogenesis; however, folate and other one-carbon related biomarkers were not associated with colon or rectal cancer.
Colorectal neoplasms; folic acid; vitamin B 6; vitamin B 12; riboflavin; homocysteine
An adverse hematological interaction between vitamins E and K has been reported, primarily in patients on anticoagulants. However, little is known regarding circulating levels or tissue concentrations of vitamin K in response to vitamin E supplementation. The purpose of this study was to examine the effect of different levels of dietary α-tocopherol on phylloquinone and menaquinone-4 concentrations, while maintaining a constant intake of phylloquinone, in rat tissues.
Male 4-wk old Fischer 344 rats (n = 33) were fed one of 3 diets for 12 wk: control (n = 13) with 30 mg all-rac-α-tocopherol acetate/kg diet; vitamin E-supplemented (n = 10) with 100 mg all-rac-α-tocopherol acetate/kg diet; and vitamin E-restricted (n = 10) with <10 mg total tocopherols/kg diet. All 3 diets contained 470 ± 80 μg phylloquinone/kg diet.
Phylloquinone concentrations were lower (P ≤ 0.05) in the vitamin E-supplemented compared to the vitamin E-restricted group (mean ± SD spleen: 531 ± 58 vs.735 ± 77; kidney: 20 ± 17 vs. 94 ± 31, brain: 53 ± 19 vs.136 ± 97 pmol/g protein respectively); no statistically significant differences between groups were found in plasma, liver or testis. Similar results were noted with menaquinone-4 concentrations in response to vitamin E supplementation.
There appears to be a tissue-specific interaction between vitamins E and K when vitamin E is supplemented in rat diets. Future research is required to elucidate the mechanism for this nutrient-nutrient interaction.
The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with α-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on α-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of α-tocopherol decrease the blood and tissue levels of δ-tocopherols. It has been suggested that γ-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a γ-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a γ-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.
The uterine cervix is the second most common site of cancer among Indian women.Though the human papillomavirus has been demonstrated to be a causative agent for this cancer, a variety of other risk factors are in play, such as sexual and reproductive patterns, socioeconomic, hygienic practices, and diet. The accumulated evidence suggests that cervical cancer is preventable and is highly suitable for primary prevention. The dietary intake of antioxidants and vitamins like vitamin A, carotenoids, vitamin C, folacin and tocopherol is found to have protective effects against cancer of the cervix. Dietary data regarding cervical cancer are still scanty.
The present study was therefore undertaken to study the dietary pattern among uterine cervical cancer patients and normal controls.
Materials and Methods:
A total of 60 consecutive patients and 60 controls were enrolled from a referral hospital during the year 2004. A schedule inclusive of the food frequency pattern and 24-h dietary recall along with the general information was administered to all the enrolled subjects to describe findings on the food consumption pattern along with other important factors.
The mean intake of energy, protein, vitamins, etc., between the cases and controls was not significantly different except for the vitamin C level. Serum vitamin E was found to have lower average in patients as compared to controls. The nutrient intake of cervical cancer patients and controls was grossly deficient in the socioeconomic group studied. With regard to the macronutrient intake, calorie and protein intakes showed a deficit of around 50% when compared to RDA.
The food consumption profile was not significantly different between cervical cancer patients and normal controls.
Cervical cancer; food consumption; low socioeconomic women
Assessments by the handful of prospective studies of the association of serum antioxidants and breast cancer risk have yielded inconsistent results. This multiethnic nested case-control study sought to examine the association of plasma carotenoids, retinol, and tocopherols with postmenopausal breast cancer risk.
From the biospecimen subcohort of the Multiethnic Cohort Study, 286 incident postmenopausal breast cancer cases were matched to 535 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection and hours of fasting. We measured prediagnostic circulating levels of individual carotenoids, retinol, and tocopherols. Conditional logistic regression was used to compute odds ratios and 95% confidence intervals.
Women with breast cancer tended to have lower levels of plasma carotenoids and tocopherols than matched controls, but the differences were not large or statistically significant and the trends were not monotonic. No association was seen with retinol. A sensitivity analysis excluding cases diagnosed within 1 year after blood draw did not alter the findings.
The lack of significant associations in this multiethnic population is consistent with previously observed results from less racially-diverse cohorts and serves as further evidence against a causal link between plasma micronutrient concentrations and postmenopausal breast cancer risk.
Approximately 40% of Americans take dietary supplements, including vitamin E (α-tocopherol). Unlike other fat-soluble vitamins, α-tocopherol is not accumulated to toxic levels. Rather tissue levels are tightly regulated, in part via increased hepatic metabolism and excretion that could, theoretically, alter metabolism of drugs, environmental toxins and other nutrients. To date, in vivo subcellular location(s) of α-tocopherol metabolism have not been identified. The proposed pathway of α-tocopherol metabolism proceeds via ω-hydroxylation to 13′-OH-α-tocopherol, followed by successive rounds of β-oxidation to form α-CEHC. To test the hypothesis that α-tocopherol ω-hydroxylation occurs in microsomes while β-oxidation occurs in peroxisomes, rats received daily injections of vehicle, 10 mg α-tocopherol or 10 mg trolox/100 g body wt for 3 days, then microsomes, mitochondria and peroxisomes were isolated from liver homogenates. Homogenate α-tocopherol levels increased 16-fold in α-tocopherol-injected rats, while remaining unchanged in trolox- or vehicle-injected rats. Total α-tocopherol recovered in the three subcellular fractions represented 93 ± 4% of homogenate α-tocopherol levels. In α-tocopherol-injected rats, microsome α-tocopherol levels increased 28-fold, while mitochondria and peroxisome levels increased 8- and 3-fold, respectively, indicating greater partitioning of α-tocopherol to the microsomes with increasing liver α-tocopherol. In α-tocopherol-injected rats, microsome 13′-OH-α-tocopherol levels increased 24-fold compared to controls, and were 7-fold greater than 13′-OH-α-tocopherol levels in peroxisome and mitochondrial fractions of α-tocopherol-injected rats. An unexpected finding was that α-CEHC, the end product of α-tocopherol metabolism, was found almost exclusively in mitochondria. These data are the first to indicate a mitochondrial role in α-tocopherol metabolism.
vitamin E; cytochrome P450; xenobiotic metabolism; mitochondria; peroxisome; β-oxidation; ω-oxidation; CYP
Vitamin D may protect against several cancers, but data regarding the association between circulating vitamin D and bladder cancer are limited.
Within the ATBC Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D (25(OH)D)(i.e., <25, 25 – <37.5, 37.5 – <50, ≥ 50 nmol/L), and by season-specific quartiles.
After multivariable adjustment, we found lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (OR, 95% CI vs. ≥ 50 nmol/L; <25 nmol/L: 1.85, 1.11 – 3.08; 25 – <37.5 nmol/L: 1.87, 1.09 – 3.20; 37.5 – <50 nmol/L: 1.81, 1.06 – 3.08; p-trend=0.02). Similarly increased risks for the lowest vitamin D category were observed when season-specific quartiles were used (OR, 95% CI Q1 vs. Q4: 1.63, 0.96 – 2.75, p-trend=0.03).
In this prospective study of male smokers, lower serum 25(OH)D was associated with an increased risk of bladder cancer. Future studies should examine the association in other populations, especially non-smokers and women.
Urinary bladder neoplasms; 25-hydroxyvitamin D; Case-control studies
We examined the relation between dietary fruit and vegetables, carotenoids and vitamin intakes and the risk of bladder cancer among male smokers in a prospective cohort study. Over a median of 11 years, we followed 27 111 male smokers aged 50–69 years who were initially enrolled in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. During this period, 344 men developed bladder cancer. All of these men had completed a 276-food item dietary questionnaire at baseline. Cox proportional hazards models were used to estimate the relative risks and 95% confidence intervals and to simultaneously adjust for age, smoking history, energy intake and intervention group. Consumption of fruits and vegetables was not associated with the risk of bladder cancer (relative risk=1.28; 95% confidence intervals CI: 0.89–1.84, for highest vs lowest quintile). Similarly, no associations were observed for groups of fruits or vegetables (berries and cruciferous vegetables), or for specific fruits and vegetables. Dietary intakes of alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, beta-cryptoxanthin, vitamins A, E, and C, and folate were not related to the risk of bladder cancer. These findings suggest that fruit and vegetable intakes are not likely to be associated with bladder cancer risk. However, these results may not be generalisable to non-smokers.
British Journal of Cancer (2002) 87, 960–965. doi:10.1038/sj.bjc.6600604 www.bjcancer.com
© 2002 Cancer Research UK
vitamins; carotenoids; fruit; vegetables; bladder cancer; cohort studies; epidemiology