Karla A. Lawson

Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study.

Supplemental vitamin E (α-tocopherol) has been linked to lower prostate cancer incidence in one randomized trial and several, although not all, observational studies. The evidence regarding dietary intake of individual vitamin E isoforms and prostate cancer is limited and inconclusive, however. We prospectively examined the relations of supplemental vitamin E and dietary intakes of α-, β-, γ-, and δ- tocopherols to prostate cancer risk among 295,344 men, ages 50 to 71 years and cancer-free at enrollment in 1995 to 1996, in the NIH-AARP Diet and Health Study. At baseline, participants completed a questionnaire that captured information on diet, supplement use, and other factors. Proportional hazards models were used to estimate relative risks (RR) and 95% confidence intervals (95% CI) of prostate cancer. During 5 years of follow-up, 10,241 incident prostate cancers were identified. Supplemental vitamin E intake was not related to prostate cancer risk (for >0-99, 100-199, 200-399, 400-799, and ≥800 IU/d versus never use: RR, 0.97, 0.89, 1.03, 0.99, and 0.97 (95% CI, 0.87-1.07) respectively; Ptrend = 0.90). However, dietary γ-tocopherol, the most commonly consumed form of vitamin E in the United States, was significantly inversely related to the risk of advanced prostate cancer (for highest versus lowest quintile: RR, 0.68; 95% CI, 0.56-0.84; Ptrend = 0.001). These results suggest that supplemental vitamin E does not protect against prostate cancer, but that increased consumption of γ-tocopherol from foods is associated with a reduced risk of clinically relevant disease. The potential benefit of γ-tocopherol for prostate cancer prevention deserves further attention. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1128–35)

History of diabetes mellitus and subsequent prostate cancer risk in the NIH-AARP Diet and Health Study.

ObjectiveA history of diabetes has been hypothesized to decrease prostate cancer risk, but studies have not always considered confounding or effect modification by dietary or lifestyle factors.MethodsWe examined the association between diabetes history and subsequent prostate cancer risk in 328,316 men enrolled in the NIH-AARP Diet and Health Study. Participants were ages 50–71 years and without a prostate cancer diagnosis at baseline in 1995. A prior history of physician-diagnosed diabetes was assessed using a self-administered mailed questionnaire. Cases of prostate cancer were ascertained by matching the cohort to state cancer registries. Multivariable relative risks (RR) and 95% confidence intervals (CI) of prostate cancer were estimated using Cox regression.ResultsDuring 5 years and 1,432,676 person-years of follow-up, 11,193 prostate cancer cases were ascertained. The age-adjusted and multivariable RRs of prostate cancer comparing men with diabetes to those without diabetes were 0.69 (95% CI = 0.64, 0.74) and 0.71 (95% CI = 0.66, 0.76), respectively, indicating no important confounding. The inverse association between diabetes and prostate cancer was particularly strong among men in the highest category of routine physical activity at work or home (RR = 0.41; 95% CI = 0.23, 0.74; p value for test of interaction = 0.03). Findings were similar for organ-confined and advanced prostate cancer.ConclusionResults from this large prospective study suggest that a history of diabetes is associated with a decreased risk of prostate cancer. The relationship strengthened with high levels of routine physical activity. Because increased physical activity is associated with lower circulating levels of insulin and testosterone, our findings support a role of hypoinsulinemia and low androgenicity linking diabetes to decreased prostate cancer risk.

Serum and Dietary Vitamin E in Relation to Prostate Cancer Risk

α-Tocopherol supplementation (50 mg daily for 5-8 years) reduced prostate cancer incidence by 32% in the α-Tocopherol, β-Carotene Cancer Prevention Study. We investigated whether serum α-tocopherol or intake of vitamin E (eight tocopherols and tocotrienols) was associated with prostate cancer risk with up to 19 years of follow-up in the α-Tocopherol, β-Carotene Cancer Prevention Study cohort. Of the 29,133 Finnish male smokers, ages 50 to 69 years recruited into the study, 1,732 were diagnosed with incident prostate cancer between 1985 and 2004. Baseline serum α-tocopherol was measured by high-performance liquid chromatography and the components of vitamin E intake were estimated based on a 276-item food frequency questionnaire and food chemistry analyses. Proportional hazard models were used to determine multivariate-adjusted relative risks (RR) and 95% confidence intervals (95% CI). Higher serum α-tocopherol was associated with reduced risk of prostate cancer (RR, 0.80; 95% CI, 0.66-0.96 for highest versus lowest quintile; Ptrend = 0.03) and was strongly and inversely related to the risk of developing advanced disease (RR, 0.56; 95% CI, 0.36-0.85; Ptrend = 0.002). The inverse serum α-tocopherol-prostate cancer association was greater among those who were supplemented with either α-tocopherol or β-carotene during the trial. There were no associations between prostate cancer and the individual dietary tocopherols and tocotrienols. In summary, higher prediagnostic serum concentrations of α-tocopherol, but not dietary vitamin E, was associated with lower risk of developing prostate cancer, particularly advanced prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1253–9)

Differential Response of Human Ovarian Cancer Cells to Induction of Apoptosis by Vitamin E Succinate and Vitamin E Analogue, α-TEA

A vitamin E derivative, vitamin E succinate (VES; RRR-α-tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (α-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with α-TEA exhibiting greater proapoptotic effects. Although both VES and α-TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only α-TEA is an effective inducer of apoptosis. VES or α-TEA treatment of cp70 cells with 5, 10, or 20 μg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by α-TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of α-TEA were demonstrated by high-performance liquid chromatography analyses that showed α-TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR-α-tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show α-TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR-α-tocopherol, an ineffective apoptotic-inducing agent.

Vitamin E and cancer

Perhaps not surprisingly, vitamin E which has been touted to be potentially beneficial for a variety of disorders, including cancer, heart disease, and even Alzheimers disorder, based on its function as an antioxidant has failed to withstand the scrutiny of recent, double-blinded, placebo-controlled clinical trials, including failure to provide science-based support for vitamin E as a potent anticancer agent. Although less studied, vitamin E forms other than RRR-alpha-tocopherol or synthetic all-rac-alpha-tocopherol show promise as anticancer agents in preclinical studies. This chapter will (1) review basic information about natural and synthetic vitamin E compounds as well as vitamin E analogues, (2) summarize the current status of human intervention trials, (3) review data from preclinical cell culture and animal model studies of vitamin E compounds and novel vitamin E-based analogues in regards to future potential for cancer treatment, and (4) summarize some of the insights that have been gained into the anticancer mechanisms of action of vitamin E-based compounds which are providing interesting insights into their potent proapoptotic effects, which include restoration of apoptotic signaling pathways and blockage of prosurvival signaling events.

Screening, Brief Intervention, and Referral for Alcohol Use in Adolescents: A Systematic Review

BACKGROUND AND OBJECTIVE: Alcohol use by adolescents is widespread and is connected to a number of negative health and social outcomes. Adolescents receiving emergent care for injuries are often linked with risky use of alcohol. The trauma system has widely adopted the use of screening, brief intervention, and referral to treatment (SBIRT) for preventing alcohol-related injury recidivism and other negative outcomes. The purpose of this article is to review the evidence around SBIRT with adolescent patients in acute care settings. METHODS: This article reviews 7 randomized controlled trials evaluating risky drinking interventions among adolescent patients in acute care settings. All studies took place in the emergency departments of level I trauma centers. RESULTS: Four of the 7 studies reviewed demonstrated a significant intervention effect; however, no one intervention reduced both alcohol consumption and alcohol-related consequences. Two of these 4 studies only included patients ages 18 and older. Subgroup analyses with adolescents engaged in risky alcohol-related behaviors, conducted in 2 of the studies, showed significant intervention effects. Five studies showed positive consumption and/or consequences for all study participants regardless of condition, suggesting that an emergent injury and/or the screening process may have a protective effect. CONCLUSIONS: Based on existing evidence, it is not clear whether SBIRT is an effective approach to risky alcohol use among adolescent patients in acute care. Additional research is needed around interventions and implementation.

Comparison of Vitamin E Derivatives α-TEA and VES in Reduction of Mouse Mammary Tumor Burden and Metastasis

A novel nonhydrolyzable ether derivative of RRR-α-tocopherol, RRR-α-tocopherol ether acetic acid analog [2, 5, 7, 8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (α-TEA)], and a hydrolyzable ester derivative RRR-α-tocopheryl succinate (vitamin E succinate; VES) inhibited BALB/c mouse 66cl-4-GFP mammary tumor cell growth in vitro and in vivo. Treatment of 66cl-4-GFP cells in culture with α-TEA or VES Induced dose-dependent DNA synthesis arrest and apoptosis and inhibited colony formation. Liposomal formulations of α-TEA delivered orally or by aerosol significantly reduced subcutaneous 66cl-4-GFP tumor burden and metastasis to lung and lymph nodes. Liposomal formulations of VES delivered by aerosol significantly reduced tumor burden and lung metastasis, but not lymph node metastasis. Unlike α-TEA, VES was ineffective in reducing tumor burden and metastasis to lungs and lymph nodes when administered orally. Analyses of tumor sections showed that α-TEA delivered by either method significantly reduced tumor cell proliferation as measured by KI67, and increased apoptosis as measured by terminal deoxynucleotldyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), whereas VES delivered by aerosol reduced tumor cell proliferation and increased apoptosis, but not significantly. In summary, the nonhydrolyzable ether vitamin E derivative α-TEA was effective in reducing tumor burden and metastasis when delivered either by aerosol or orally, whereas the hydrolyzable ester vitamin E derivative VES was effective only when delivered by aerosol.

Vitamin E analog α-TEA and celecoxib alone and together reduce human MDA-MB-435-FL-GFP breast cancer burden and metastasis in nude mice

Abstractα-TEA, a nonhydrolyzable ether analog of vitamin E (RRR-α-tocopherol), and celecoxib, a specific COX-2 inhibitor, were delivered separately or in combination to investigate their anticancer properties, using MDA-MB-435-FL-GFP human breast cancer xenografts in nude mice. Liposomal formulated α-TEA administered as an aerosol and celecoxib fed at 500 or 1250 mg/kg diet for 31 days separately or in combination significantly reduced tumor volume in comparison to control (p < 0.001 for all treatment groups). Of special note, the combinations of α-TEA + celecoxib (1250) inhibited tumor volume significantly better than either single treatment (p < 0.001 and p < 0.001). Average number of macroscopic lung metastases were significantly reduced in all treatment groups in comparison to control, with the exception of celecoxib (500). Mean numbers of microscopic lung and lymph node metastases in all treatment groups were significantly lower than control. Furthermore, the mean number of microscopic lung metastases in the α-TEA+celecoxib (1250) group were significantly lower than either separate treatment. Analyses of 5 μm tumor sections showed that all treatments, with the exception of celecoxib (500) alone, significantly enhanced apoptosis (TUNEL) and significantly decreased cell proliferation (Ki-67). α-TEA and α-TEA + celecoxib (1250) treatments significantly reduced blood vessel density (CD-31) in comparison to control. These data show promise for combination α-TEA + celecoxib chemotherapy for breast cancer.

Association of Variants in Two Vitamin E Transport Genes with Circulating Vitamin E Concentrations and Prostate Cancer Risk

Significant reductions in prostate cancer incidence and mortality were observed in men randomized to receive 50 mg supplemental vitamin E (alpha-tocopherol) per day in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We hypothesized that variation in key vitamin E transport genes might directly affect prostate cancer risk or modify the effects of vitamin E supplementation. Associations between prostate cancer risk and 13 polymorphisms in two genes, TTPA and SEC14L2, were examined in 982 incident prostate cancer cases and 851 controls drawn from the ATBC Study. There was no association between the genetic variants and prostate cancer risk. Significant interactions were observed, however, between two variants in SEC14L2 (IVS11+931A>G and IVS11-896A>T) and the trial alpha-tocopherol supplement such that vitamin E supplementation reduced prostate cancer risk among men who were homozygous for either common allele [odds ratios (OR) and 95% confidence intervals (95% CI), 0.52 (0.30-0.90) and 0.64 (0.46-0.88), respectively] and nonsignificantly increased risk among those who carried one or two copies of either variant allele [ORs and 95% CIs, 1.27 (0.90-1.79) and 1.21 (0.96-1.52), respectively; both P for interaction < 0.05]. Genotype-phenotype analyses revealed significant but modest differences in baseline circulating concentrations of alpha-tocopherol and serum responses to the vitamin E supplementation for several polymorphisms. This study shows that genetic variation in TTPA and SEC14L2 is associated with serum alpha-tocopherol but does not have a direct effect on prostate cancer. Our results do, however, suggest that polymorphisms in SEC14L2 may modify the effect of vitamin supplementation regimens on prostate cancer risk.

α-TEA plus cisplatin reduces human cisplatin-resistant ovarian cancer cell tumor burden and metastasis

A novel nonhydrolyzable ether-linked acetic acid analog of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (α-TEA) in combination with cisplatin, reduces tumor burden of A2780/cp70 (cp70) cisplatin-resistant human ovarian cancer cells xenografted into immune compromised nude mice. Two xenograft studies were conducted using cp70 cells stably expressing green fluorescent protein (cp70-GFP) subcutaneously transplanted into NU/NU mice. For studies 1 and 2, α-TEA was formulated in liposomes and delivered by aerosol such that approximately 36 μg and 72 μg of α-TEA were deposited in the respiratory tract of each mouse each day, respectively. Cisplatin at 5 mg/kg was administered by intraperitoneal injections once weekly for the first 3 weeks in Study 1 and on the third and 10th days following treatment initiation in Study 2. The combination α-TEA + cisplatin treatment reduced tumor burden and metastasis of cp70-GFP cells in comparison to control mice or mice treated with α-TEA or cisplatin singly. A significant reduction (P < 0.001) in growth of subcutaneous transplanted tumors was obtained with α-TEA + cisplatin for both studies. Visible metastases were observed in the lungs of animals from control and cisplatin-treated groups but not in animals from the α-TEA- or α-TEA + cisplatin–treated groups. The α-TEA + cisplatin significantly reduced the total number of lung and axillary lymph node micrometastasis (P < 0.03 and P < 0.0001, respectively). Analyses of tumor sections showed the α-TEA + cisplatin treatment group, in comparison to control, to have a significantly lower level of cell proliferation (Ki-67 staining; P < 0.0001) and a significantly higher level of apoptosis (terminal deoxynucleotidyl transferase–mediated nick end labeling [TUNEL]; P < 0.0001). In summary, combinations of α-TEA + cisplatin significantly reduced tumor burden and metastases in a xenograft model of cisplatin-resistant human ovarian cancer cells. These data show promise for combination α-TEA + cisplatin chemotherapy for ovarian cancer.