COMT Effects on Vitamin E and Colorectal Cancer, in-vitro and in Two Randomized Trials (P15-005-19)

Hall K, Weinstein S, Buring J, Mukamal K, Moorthy MV, Ridker P, Albanes D, Cook N, Chasman D, Sesso H

Curr Dev Nutr. 2019 Jun 13;3(Suppl 1). pii: nzz037.P15-005-19. doi: 10.1093/cdn/nzz037.P15-005-19. eCollection 2019 Jun.

Abstract

OBJECTIVES:

Despite promising observational data and compelling mechanisms of action, vitamin E has failed to demonstrate evidence of benefit in randomized clinical trials (RCTs). In two large long-term placebo-controlled RCTs, we reported that vitamin E effects on total cancer were modified by genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Here we investigate COMT effects on colorectal cancer (CRC) in the two RCTs and a CRC cell line.

METHODS:

We analyzed COMT rs4680 association with rates of CRC in the Women’s Health Study (WHS), N = 23,294 and a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC). Cell survival and apoptosis were examined in-vitro in HCT116 cells treated with increasing doses of vitamin E when COMT gene expression was inhibited by silencing RNA (siRNA).

RESULTS:

Rates of CRC were higher with randomized vitamin E compared to placebo among COMT high-activity val/val homozygotes in ATBC (HR, [CI] = 3.00, [1.48-6.09]), but not WHS (HR, [CI] = 0.99, [0.63-1.57]). Among low-activity met/met homozygotes randomized to vitamin E compared to placebo, rates of CRC were borderline lower in WHS (HR, [CI] = 0.66, [0.44-1.01]), but not in ATBC (HR, [CI] = 0.93, [0.63-1.62]).In cell culture, vitamin E at 3 µg/ml and 10 µg/mL had no effect on cell viability or apoptosis. However, silencing COMT resulted in a modest apoptotic effect that vitamin E enhanced in a dose-dependent manner. Human apoptosis arrays indicated that in the absence of COMT expression, vitamin E induced protein expression related to the intrinsic apoptotic pathway through p53 activation, dysregulation of Bcl-2 family protein expression and down-regulation of IAP family protein expression.

CONCLUSIONS:

Differential COMT effects on vitamin E and CRC were similar to those previously reported for all invasive cancers, but were only significant for val/val homozygotes. Further, inhibiting COMT in the presence of vitamin E in a CRC in-vitro model, recapitulated the RCT observation that among individuals homozygous for the low-activity allele (met/met) vitamin E tended to reduce invasive cancer and here CRC.

Husain K, Zhang A, Shivers S, Davis-Yadley A, Coppola D, Yang CS, Malafa MP

Cancer Prev Res (Phila). 2019 Jun;12(6):357-366. doi: 10.1158/1940-6207.CAPR-18-0290. Epub 2019 Apr 2.

Abstract

This study evaluated the preclinical activity of δ-tocotrienol (DT3), a bioactive form of vitamin E, in the inhibition of colorectal cancer growth and development in vitro and in vivo DT3 is the most bioactive isomer of vitamin E in inhibiting growth of colorectal cancer cells. However, it had little effect on the proliferation of normal colon mucosal cells NCM460. In HCT-116 and SW-620 colorectal cancer cells, DT3 (50 μmol/L) significantly inhibited malignant transformation (P < 0.02, P < 0.001), cell migration (P < 0.02, P < 0.05), and invasion (P < 0.05, P < 0.01) compared with vehicle. DT3 inhibited markers for epithelial (E-cadherin) to mesenchymal (vimentin) transition, metastasis (matrix metalloproteinase 9), angiogenesis VEGF, inflammation (NF-κB), and Wnt signaling (β-catenin) compared with vehicle in colorectal cancer cells. DT3 induced apoptosis selectively in colorectal cancer cells (SW-620 cells, HCT-116 cells, and HT-29) without affecting the normal colon cells. In the azoxymethane-induced colorectal carcinogenesis model in rats, DT3 (200 mg/kg orally twice a day) for 20 weeks significantly inhibited colorectal polyps by 70% and colorectal cancer by almost 99% compared with the vehicle treatment group (P < 0.02, P< 0.001), and the cancer inhibition effect was more potent than sulindac (50%). Taken together, these data demonstrate that DT3 is a potential chemopreventive agent in colorectal cancer, warranting further investigation into its clinical use in the prevention and treatment of colorectal cancer.

Tobias DK

Circ Res. 2019 Jun 21;125(1):41-42. doi: 10.1161/CIRCRESAHA.119.315285. Epub 2019 Jun 20.

Abstract

Huang et al of the ATBC study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) reported a significant relationship between serum α-tocopherol with lower risks of all-cause and cause-specific mortality in men. The ATBC cohort analysis included 29 092 male smokers aged 50 to 69 years at baseline, and 23 787 deaths were observed over 31 years of follow-up. Compared with the bottom 20% of serum α-tocopherol concentrations, men in the top 20% experienced a 22% lower risk of total mortality. Their results were robust to several sensitivity and subgroup analyses and persisted over 31 years of observation.

Huang J, Weinstein SJ, Yu K, Männistö S, Albanes D

Circ Res. 2019 Jun 21;125(1):29-40. doi: 10.1161/CIRCRESAHA.119.314944. Epub 2019 May 6.

Abstract

RATIONALE:

Although there has been a long-standing interest in the human health effects of vitamin E, a comprehensive analysis of the association between circulating vitamin E and long-term mortality has not been conducted.

OBJECTIVE:

Determine whether serum α-tocopherol (the predominant form of vitamin E) is related to long-term overall and cause-specific mortality and elucidate the dose-response relationships with better quantification of the associations.

METHODS AND RESULTS:

We conducted a biochemical analysis of 29 092 participants in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) that originally tested vitamin E and β-carotene supplementation. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and during a 30-year follow-up we identified 23 787 deaths, including deaths from cardiovascular disease (9867), cancer (7687), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2698). After adjusting for major risk factors, we found that men with higher serum α-tocopherol had significantly lower all-cause mortality (hazard ratios=0.83, 0.79, 0.75, and 0.78 for quintile 2 (Q2)-Q5 versus Q1, respectively; P_trend<0.0001), and significantly decreased mortality from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, and other causes, with risk reductions from 17% to 47% for the highest versus lowest quintile. The α-tocopherol association with overall mortality was similar across subgroups of smoking intensity, years of smoking, alcohol consumption, trial supplementation, and duration of follow-up. The association was, however, significantly modified by baseline age and body mass index, with stronger inverse associations for younger men and men with a lower body mass index ( P_interaction≤0.006).

CONCLUSIONS:

In this long-term prospective cohort study, higher baseline serum α-tocopherol biochemical status was associated with lower risk of overall mortality and mortality from all major causes. Our data support the long-term health benefits of higher serum α-tocopherol for overall and chronic disease mortality and should be replicated in other more diverse populations.

Chen Y, Li C, Song P, Yan B, Yang X, Wu Y, Ma P

Food Chem Toxicol. 2019 Jun 20;132:110600. doi: 10.1016/j.fct.2019.110600. [Epub ahead of print]

Abstract

Diisononyl phthalate (DIDP) is commonly used as a plasticizer in industrial and consumer products, however, its toxicity remains unclear. This study investigated the possible involvement of oxidative stress in DIDP-induced liver and kidney toxicity. Liver function and kidney function, tissue lesions, oxidative stress biomarkers, inflammatory mediators and apoptosis factors were investigated in this study. The results showed that oral exposure to DIDP induced a marked increase in lever of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urinary nitrogen (UREA) and creatinine (CREA), decrease in albumin (ALB) level, as well as causing hepatic and renal histopathological change. Investigation of the role of oxidative stress pathways showed that DBP exposure could lead to a significant increase in levels of reactive oxygen species (ROS), malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB), while a decrease in glutathione (GSH) levels were observed. Administration of vitamin E to DIDP-treated mice restored these biochemical parameters to within normal levels, and resulted in less damage to livers and kidneys. Overall, these results suggest that the oxidative stress pathway is involved in DIDP-induced toxicity.

Akçay H, Kuru K, Tatar B, Şimşek F

J Craniofac Surg. 2019 Jun 20. doi: 10.1097/SCS.0000000000005685. [Epub ahead of print]

Abstract

The long consolidation period of distraction osteogenesis (DO) may lead to complications such as pain, infection, fracture, scar formation, malunion and delayed union. The aim of this study was to evaluate the effect of systemic Vitamin E application during mandibular DO on new bone regeneration in a rabbit model. 16 adult male 8 months old New Zealand rabbits underwent mandibular lengthening with a distractor for the study. After the latency period of 5 days, the distractor was activated at a rate of 0.5 mm/12 hours for 7 days. Experimental animals received 200 mg/kg injections of α-tocopherol intraperitoneally for 7 days starting with the operation. After the consolidation period of 30 days, rabbits were sacrificed. Lengthened mandibles were obtained and subjected to dual-energy X-ray absorptiometry (DXA), radiologic and histomorphometric analysis. Statistically, bone mineral density and bone mineral content values were found to be significantly higher in the experimental group than the control group during DXA analysis. Rabbits in the experimental group had statistically higher scores in terms of osteoblast, osteoclast, vessel numbers and newly formed bone area than the control group. Results of the present study showed that systemic Vitamin E application during DO may stimulate new bone formation in rabbits and thus results in shortened treatment time.

Piran S, Sarmasti S, Shabani M, Kakavandi N, Hosseni B, Khosravi M, Resaee S, Soltanmohammadi E, Naseri F, Ghasempour G, Mohammadi A, Najafi M

Recent Pat Food Nutr Agric. 2019 Jun 18. doi: 10.2174/2212798410666190618152134. [Epub ahead of print]

Abstract

METHODS:

A total of 120 overweight subjects participated in this study. The circulating PCSK9 and vitamin D were measured by ELISA technique. The serum vitamin A and vitamin E amounts were simultaneously measured by HPLC method. The serum small dense LDL-Cholesterol (sdLDL-C) values were evaluated using heparin-Mg2+ precipitation technique. The lipid profile was measured by routine laboratory techniques.

RESULTS:

The serum vitamin E values correlated significantly to vitamin A (r=0.47, P= 0.0001), VLDL-C (r= 0.30, P= 0.002), total cholesterol (r=0.309, P= 0.001), PCSK9 (r=0.233, P=0.01) and total triglyceride (r= 0.61, P= 0.0001) values. The circulating PCSK9 values correlated significantly to LDL-C (r=0.17, P=0.05) and total cholesterol (r=0.23, P=0.009) values. However, there were not correlations between the levels of serum D and A vitamins, the serum LDL-C, sdLDL-C and total cholesterol values.

CONCLUSION:

The data showed the correlations between serum vitamin E and PCSK9-related LDL-C values lower than the normal range. Furthermore, the results suggested a nutritional need on the patents considering supplementation or fortification of vitamin E for the overweight subjects with higher LDL-C levels.

Hajizadeh K, Alizadeh Charandabi SM, Hasanzade R, Mirghafourvand M

Complement Ther Med. 2019 Jun;44:1-8. doi: 10.1016/j.ctim.2019.03.014. Epub 2019 Mar 22.

Abstract

OBJECTIVES:

A systematic review was conducted to assess the effect of vitamin E on the severity and duration of Cyclic Mastalgia compared to vitamin B6, fish oil, herbal medicines and placebo.

DESIGN:

A systematic review and meta-analysis of clinical trials.

METHODS:

A search was carried out in PubMed, Cochrane Library, Embase, Scopus and Google Scholar and Persian databases for articles published from 1980 to 2018. The data obtained were analyzed in RevMan and reported in forest plots. The Odds Ratio (OR) was used to find the effect for the dichotomous data and the Standardized Mean Difference (SMD) for the continuous data. The heterogeneity of the studies was assessed using I² and the Random Effects Model was used instead of the Fixed Effects Model if I²>25%.

RESULTS:

A total of 1051 titles and abstracts were extracted. Fourteen articles ultimately remained, and 11 of them were entered into the meta-analysis. The meta-analysis showed significant differences between vitamin E and placebo in the severity (SMD=-0.51; 95% CI=-0.21 to -0.82) and duration (MD=-1.47; 95% CI=-0.91 to -2.57) of cyclic mastalgia, although herbal medicines had a greater effect on the severity of mastalgia than vitamin E (SMD = 0.51, 95% CI = 0.06 to 0.96).

CONCLUSION:

Although herbal medicines are more effective than vitamin E, vitamin E reduces both the severity and duration of the disorder compared to placebos, which only reduce its severity, and can therefore be considered a treatment with minimum side-effects. Due to the high heterogeneity of the studies, the researchers recommend further research on the subject using a standard tool based on the CONSORT statement.

Kara Y, Akyuz F

Andrologia. 2019 Jun 17:e13355. doi: 10.1111/and.13355. [Epub ahead of print]

Abstract

Testis is a rich organ with blood vessels. For this reason, it is possible that the toxic substances of the cigarette carried in the blood change the balance between the oxidant and the antioxidant system in this organ. In this study, it was aimed to investigate the effects of N-nitro L-arginine methyl ester and α-tocopherol on testicular oxidative stress caused by exposure to cigarette smoke. 45 wistar male rats were used in the study. Five groups were formed: control, cigarette smoke, cigarette smoke + α-tocopherol, cigarette smoke + N-nitro L-arginine methyl ester and cigarette smoke + α-tocopherol + N-nitro L-arginine methyl ester. Biochemical and histological evaluations were performed to determine the damage caused by cigarette smoke. It was observed that there were structural and functional disturbances at the cellular and hormonal level in the smoking group. Biochemical evaluations showed that cellular damage was reduced in treatment groups. Histological examinations were revealed that the damage caused by cigarette smoke exposure was eliminated in treatment groups. As a result of our study, we think that oxidative damage and hormonal irregularity in the testes tissue caused by cigarette smoke exposure can be improved with α-tocopherol and N-nitro L-arginine methyl ester application.

Ranard K, Kuchan M, Erdman J Jr

Curr Dev Nutr. 2019 Jun 13;3(Suppl 1). pii: nzz048.P11-134-19. doi: 10.1093/cdn/nzz048.P11-134-19. eCollection 2019 Jun.

Abstract

OBJECTIVES:

Humans with vitamin E (α-tocopherol, αT) deficiency develop neurological disorders. Similarly, α-tocopherol transfer protein knockout (Ttpa^-/- ) mice have low vitamin E status and exhibit neurodegeneration with age. Shifts in the transcriptome may precede behavioral manifestations of vitamin E deficiency, but it is unknown how early abnormalities occur. Aberrations during brain development could have lifelong implications. The study objective was to determine how αT restriction during early-life affects the expression of pre-selected neurogenesis-related genes in the cerebellum (CB) and cerebral cortex (CC) of Ttpa^-/- weanlings.

METHODS:

Female Ttpa^+/+ (n = 9) and Ttpa^-/- (n = 10) mice were nursed by Ttpa^+/- dams until postnatal day 21. Dams were fed AIN-93G diet (75 mg αT/kg diet) during days 1-9 of gestation, and αT-stripped diet for the rest of the study. Homogenized brain tissues from 21 day old weanlings were used to measure αT concentrations via HPLC-PDA. The expression of genes critical for brain development (Rora, Shh), myelination (Plp1, Cntnap1, Mbp, Mobp, Nr1h3), synaptic function (Cplx1, Cplx2, Vamp2, Necab1, Prkcg), and αT cellular uptake (Scarb1) were measured in the CB and CC via real-time qPCR.

RESULTS:

αT levels were significantly decreased in brains of Ttpa^-/- mice (0.1 ± 0.1 nmol/g) compared to Ttpa^+/+ mice (9.8 ± 1.4 nmol/g) (P < 0.001), confirming their low αT status. Rora, Shh, Cntnap1, and Mbp were significantly upregulated (P < 0.05) in both the CB and CC of Ttpa^-/- mice, while several genes were only upregulated in one brain region (Plp1 in the CB, Mobp in the CC). Necab1 and Scarb1 were significantly downregulated in the CB of Ttpa^-/- mice (P < 0.05).

CONCLUSIONS:

αT restriction during the fetal and postnatal periods alters the expression of neurogenesis-related genes. These findings support a role for αT in brain development.