The vitamin E analogue α-TEA stimulates tumor autophagy and enhances antigen cross-presentation

The semisynthetic vitamin E derivative alpha-tocopheryloxyacetic acid (α-TEA) induces tumor cell apoptosis and may offer a simple adjuvant supplement for cancer therapy if its mechanisms can be better understood. Here we report that α-TEA also triggers tumor cell autophagy and that it improves cross-presentation of tumor antigens to the immune system. α-TEA stimulated both apoptosis and autophagy in murine mammary and lung cancer cells and inhibition of caspase-dependent apoptosis enhanced α-TEA-induced autophagy. Cell exposure to α-TEA generated double-membrane-bound vesicles indicative of autophagosomes, which efficiently cross-primed antigen-specific CD8(+) T cells. Notably, vaccination with dendritic cells pulsed with α-TEA-generated autophagosomes reduced lung metastases and increased the survival of tumor-bearing mice. Taken together, our findings suggest that both autophagy and apoptosis signaling programs are activated during α-TEA-induced tumor cell killing. We suggest that the ability of α-TEA to stimulate autophagy and enhance cross-priming of CD8(+) T cells might be exploited as an adjuvant strategy to improve stimulation of antitumor immune responses.     

β-Carotene and/or vitamin E as modulators of alkylating agents in SCC-25 human squamous carcinoma cells

Summary Dietary levels of -carotene and vitamin E have been associated with cancer prevention and to a lesser extent, with therapeutic enhancement of cancer treatment. We report on the cytotoxicity of -carotene, vitamin E, and the combination of -carotene and vitamin E in human SCC-25 squamous carcinoma cells under various environmental conditions found in solid tumor masses. -Carotene was selectively cytotoxic toward normally oxygenated cells and was generally more cytotoxic at normal pH than at acidic pH (6.45). Vitamin E was selectively cytotoxic toward normally oxygenated cells following 6 h exposure at normal pH and was generally equally cytotoxic toward normally oxygenated and hypoxic cells under the other conditions tested. -Carotene was an effective modulator of cisplatin (CDDP) cytotoxicity toward SCC-25 cells, whereas vitamin E was not. Both -carotene and vitamin E were effective modulators of melphalan cytotoxicity toward SCC-25 cells. Treatment of SCC-25 cells with -carotene (70 m, 2h) resultec in a reduction in superoxide dismutase activity, in glutathione-S-transferase activity, and in nonprotein sulfhydryl levels in the cells. Exposure to vitamin E or to a combination of -carotene and vitamin E increased the glutathione-S-transferase activity in SCC-25 cells by 40%–45% over the control value. Treatment with -carotene, vitamin E, or canthaxanthin reduced the incorporation of [³H]-thymidine into SCC-25 cells but not that into normal human karotinocytes. The most marked reduction in [³H]-thymidine incorporation into SCC-25 cells occurred following treatment with the combination of -carotene and melphalan. We hope to continue to explore the mechanisms of this effect and to study these combinations in vivo.This work was supported by NIH grant PO1-38 493, by a grant from Bristol-Mycrs-Squibb (Wallingford, Conn.), and by a grant from Cancer Prevention Technologies, Inc. (Basking Ridge, N. J.)     

Does vitamin E prevent or promote cancer?

The cancer preventive activity of vitamin E has been suggested by many epidemiologic studies. However, several recent large-scale human trials with α-tocopherol, the most commonly recognized and used form of vitamin E, failed to show a cancer preventive effect. The recently finished follow-up of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) even showed higher prostate cancer incidence in subjects who took α-tocopherol supplementation. The scientific community and the general public are faced with a question: "Does vitamin E prevent or promote cancer?" Our recent results in animal models have shown the cancer preventive activity of γ- and δ-tocopherols as well as a naturally occurring mixture of tocopherols, and the lack of cancer preventive activity by α-tocopherol. On the basis of these results as well as information from the literature, we suggest that vitamin E, as ingested in the diet or in supplements that are rich in γ- and δ-tocopherols, is cancer preventive; whereas supplementation with high doses of α-tocopherol is not.     

Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose–response meta-analysis

Background:

Epidemiological studies evaluating the association of vitamin B₆, vitamin B₁₂ and methionine with breast cancer risk have produced inconsistent results.

Methods:

Pertinent studies were identified by a search in PubMed and Web of Knowledge. Random-effect model was used. Dose–response relationship was assessed by restricted cubic spline.

Results:

The combined relative risk (95% confidence interval) of breast cancer for the highest vs lowest category of serum pyridoxal 5′-phosphate (PLP, active form of vitamin B₆) levels and dietary methionine intake was 0.80 (0.66–0.98, P=0.03) and 0.94 (0.89–0.99, P=0.03), respectively, and the associations of breast cancer with higher serum PLP levels and dietary methionine intake were significant among post-menopausal women, but not among pre-menopausal women. The inverse association between breast cancer risk and dietary vitamin B₆ intake, serum vitamin B₁₂ levels and dietary vitamin B₁₂ intake was not significant overall. Linear dose–response relationship was found, and the risk of breast cancer decreased by 23% (P<0.00) for every 100 pmol ml⁻¹ increment in PLP levels and 4% (P=0.05) for every 1 g per day increment in dietary methionine intake, respectively.

Conclusion:

Serum PLP levels and methionine intake might be inversely associated with breast cancer risk, especially among postmenopausal women, which need to be confirmed.     

Sun protection and low levels of vitamin D: are people concerned?

Objective Recent reports on the association between low serum vitamin D and increased risk of cancer raised concerns about possible adverse effects of primary prevention strategies for skin cancer. To evaluate if these reports may influence peoples’ sun protective behavior, knowledge, and attitudes to the impact of sun protection on vitamin D. Methods Within a population-based survey in Queensland, Australia (5,611 participants, mean age 50.7 years (range 20–75); 48.2% men), agreement with the statement that sun protection may result in not having enough vitamin D as well as factors associated with agreement were assessed. Results Overall, 837 (15.0%) participants agreed that sun protection may result in not having enough vitamin D, 2,163 (38.7%) neither agreed nor disagreed, and 2,591 (46.3%) disagreed with this statement. Factors associated with agreement included older age, darker skin color, and attempt to develop a suntan within the past year. Conclusion These results suggest that future sun protection campaigns may need to address the issue of vitamin D and present ways to achieve sufficient vitamin D levels without increasing sun exposure at least in countries with high UV radiation throughout the year.     

Are retinol,vitamin C,vitamin E,folate and carotenoids intake associated with bladder cancer risk? Results from the Netherlands Cohort Study

In the Netherlands Cohort Study among 120 852 subjects aged 55-69 years at baseline (1986), the association between vitamins and carotenoids intake, vitamin supplement use, and bladder cancer incidence was examined. Exposure status was measured with a food-frequency questionnaire. After 6.3 years of follow-up, data from 569 cases and 3123 subcohort members were available for case-cohort analyses. The age-, sex-, and smoking-adjusted relative risks (RRs) for retinol, vitamin E, folate, a-carotene, b-carotene, lutein and zeaxanthin, and lycopene were 1.04, 0.98, 1.03, 0.99, 1.16, 1.11, and 1.08, respectively, comparing highest to lowest quintile of intake. Only vitamin C (RR: 0.81, 95% CI: 0.61-1.07, P-trend = 0.08), and b-cryptoxanthin intake (RR: 0.74, 95% CI: 0.53-1.03, P-trend < 0.01) were inversely associated with bladder cancer risk. The association with vitamin C disappeared after adjustment for b-cryptoxanthin but not vice versa. The RRs for supplemental use of vitamin A, C or E compared to no use were around unity. We conclude that dietary or supplemental intake of vitamin A, vitamin C, vitamin E, and intake of folate, and most carotenoids are not associated with bladder cancer. In this study, only b-cryptoxanthin intake appeared to be inversely associated.     

The role of calcium and vitamin D dietary intake on risk of colorectal cancer: systematic review and meta-analysis of case–control studies

Cancer Causes & Control - The aim of this study is to analyze the current evidence about the relationships between calcium/vitamin D and CRC based on case–control studies according to...     

A population-based case–control study of carotenoid and vitamin A intake and ovarian cancer (United States)

Objective: To evaluate the association between dietary intake of carotenoids and vitamin A and the incidence of ovarian cancer. Methods: We conducted a population-based case–control study of ovarian cancer in Massachusetts and Wisconsin. Incident cases diagnosed between 1991 and 1994 were identified through statewide tumor registries. We selected community controls at random from lists of licensed drivers and Medicare recipients; 327 cases and 3129 controls were included in the analysis. Data were collected by telephone interview, which included an abbreviated food and supplement list to quantify typical consumption of carotenoids (lutein/zeaxanthin, alpha-carotene, beta-carotene), retinol and total vitamin A at 5 years prior to diagnosis in cases, or to a comparable reference date in controls. Results were adjusted for age, state, and other risk factors. Results: Participants with the highest dietary intake of lutein/zeaxanthin (24,000 g/week) experienced a 40% lower risk of ovarian cancer (95% CI = 0.36–0.99) compared to those with the lowest intake. Intake of alpha-carotene, beta-carotene, retinol and total vitamin A was unrelated to risk. Among foods, we observed non-significantly lower risks with high consumption of spinach, carrots, skim/lowfat milk and liver. Conclusion: These results support previous findings suggesting an inverse relationship between carotenoid intake and ovarian cancer risk.     

Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose–response meta-analysis

Objective  

We systematically reviewed and meta-analyzed literature examining associations of vitamin D (dietary intake, circulating 25-hydroxy-vitamin-D (25(OH)D), and 1,25-dihydroxy-vitamin-D (1,25(OH)₂D) concentrations) with prostate cancer.     

Increased sensitivity of HPV-positive head and neck cancer cell lines to x-irradiation ± Cisplatin due to decreased expression of E6 and E7 oncoproteins and enhanced apoptosis

Squamous cell carcinoma of the head and neck region (HNSCC), which is related to an infection with human papilloma virus (HPV), responds better to simultaneous radio-chemotherapy with Cisplatin based regimens than HPV-negative tumors. The underlying molecular mechanisms for this clinical observation are not fully understood. Therefore, the response of four HPV-positive (HPV+) (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (HPV-) (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) HNSCC cell lines to x-irradiation ± Cisplatin incubation in terms of clonogenic survival, cell cycle progression, protein expression (cyclin A2, cyclin E2, E6, E7, p53) and induction of apoptosis, was investigated. HPV+ cells were more radio- and chemosensitive and were more effectively sensitized to x-irradiation by simultaneous Cisplatin incubation than HPV- cell lines. HPV+ cell lines revealed an increased and prolonged G2/M arrest after irradiation, whereas Cisplatin induced a blockage of cells in S phase. In comparison to irradiation only, addition of Cisplatin significantly enhanced apoptosis especially in HPV+ cell lines. While irradiation alone increased the amount of HPV E6 and E7 proteins, both were down-regulated by Cisplatin incubation either alone or in combination with x-rays, which however did not increase the expression of endogenous p53. Our results demonstrate that cell cycle deregulation together with downregulation of HPV E6 and E7 proteins facilitating apoptosis after Cisplatin incubation promote the enhanced sensitivity of HPV+ HNSCC cells to simultaneous radio-chemotherapy. Combined effects of irradiation and Cisplatin appear to be relevant in mediating the enhanced therapeutic response of HPV-related HNSCC and are indicative of the benefit of combined modality approaches in future treatment optimization strategies.     

Are vitamin and mineral deficiencies a major cancer risk?

Diet is estimated to contribute to about one-third of preventable cancers -- about the same amount as smoking. Inadequate intake of essential vitamins and minerals might explain the epidemiological findings that people who eat only small amounts of fruits and vegetables have an increased risk of developing cancer. Recent experimental evidence indicates that vitamin and mineral deficiencies can lead to DNA damage. Optimizing vitamin and mineral intake by encouraging dietary change, multivitamin and mineral supplements, and fortifying foods might therefore prevent cancer and other chronic diseases.     

Sunlight exposure,vitamin D,and risk of non-Hodgkin lymphoma in the Nurses’ Health Study

Purpose  

Case–control studies suggest increased sun exposure reduces non-Hodgkin lymphoma (NHL) risk. Evidence from prospective cohort studies, however, is limited and inconsistent. We evaluated the association between ambient ultraviolet radiation (UV) exposure and NHL in a nationwide cohort of women, the Nurses’ Health Study (NHS).     

Expression of Cyclin E and Its Relationship with the Prognosis of Patients with Breast Cancer

Objective： To investigate the expression of cyclin E in breast cancer tissues and its relationship with prognosis of the patients with breast cancer. Methods： The expression of cyclin E, HER-2/neu, nm23-H1 and actin was detected in 80 breast cancer tissues and 18 benign breast tumor tissues by immunohistochemical methods. The relationship between cyclin E and the remaining genes or the clinical data of the patients with breast cancer was analyzed. Results： The over expression rate of cyclin E in malignant tissues was obviously higher than that in benign tumor tissues （P〈0.01）. The over expression of cyclin E in later stage of disease was higher than that in early stage of disease （P〈0.05）. The expression of cyclin E in ER positive tissues was lower than that in ER negative tissues （P〈0.05）. The expression of cyclin E in PR positive tissues and PR negative tissues had no significant difference （P〉0.05）. The expression of cyclin E in HER-2/neu positive tissues was higher than that in HER-2/neu negative tissues （P〈0.05）. And the expression of cyclin E in ER, PR and HER-2/neu all positive tissues was much higher （P〈0.01）. There was no significant difference in the expression of cyclin E between nm23-H1 positive tissues and nm23-H1 negative tissues （P〉0.05）. The expression of cyclin E in actin positive and continuous distribution tissues was lower than that in actin negative or discontinuous distribution tissues （P〈0.05）. Conclusion： The expression of cyclin E has a strong correlation to the prognosis of the patients with breast cancer.     

Plasma vitamins E and A and risk of bladder cancer: a case–control analysis

Objective  Current results on the association between serum micronutrients and bladder cancer risk have been inconsistent. We assessed plasma vitamin E (α-tocopherol, and γ-tocopherol), vitamin A (retinol), and bladder cancer risk using data collected from a case-control study. Methods  Epidemiologic data were collected via in-person interview. Plasma concentrations of α-tocopherol, γ-tocopherol, and retinol were determined by a high-performance liquid chromatography assay. Multivariate logistic regression analyses were used to estimate bladder cancer risk in association with plasma vitamins E and A. Results  386 bladder cancer patients and 389 age-, gender-, and ethnicity-matched controls were included in the study. The mean plasma α-tocopherol and retinol were significantly lower in cases than in controls (α-tocopherol: 23.93 μg/ml vs. 27.48 μg/ml, P < 0.001; retinol: 1.41 μg/ml vs. 1.53 μg/ml, P < 0.001). There was a significant reduction in bladder cancer risk associated with increasing plasma α-tocopherol level (Adjusted OR: 0.91; 95% CI: 0.85–0.97). In quartile analysis, using subjects with the lowest α-tocopherol level as the reference group, the adjusted ORs and 95% CIs for the second, third, and fourth quartiles were 0.75 (0.50–1.14), 0.69 (0.46–1.05), and 0.50 (0.32–0.78), respectively (P for trend = 0.003). Increased retinol level was also associated with reduced risk with OR of 0.57 (95% CI: 0.40–0.81). The ORs and 95% CIs for the second, third, and fourth quartiles were 0.92 (0.61–1.39), 0.66 (0.43–1.01), and 0.62 (0.40–0.95), respectively, with significant dose-response trend (P for trend = 0.01). Finally, there were significant correlations between plasma levels and dietary intakes for the three micronutrients. Conclusion  Our results suggest potential protective effect of α-tocopherol and retinol on bladder cancer risk. Future large prospective studies are needed to confirm the findings. Supported by NCI grants CA 74880 and CA 91846 All participants included have signed an informed consent to participate in this study. The authors declare no conflict of interest.     

Expression of E2F-1, Rb and ER in Peripheral Papilloma and Ductal Carcinoma in Situ of the Breast and its Significance

OBJECTIVE To investigate the correlation of E2F-1, Rb and ER expression with peripheral papilloma (Peri-PM) and ductal carcinoma in situ of the breast (DCIS), and further explore some molecular mechanisms of the canceration of Peri-PM. METHODS Imunohistochemistry was used to examine the expression of E2F-1, Rb and ER in 60 Peri-PM, 60 Peri-PM with atypical ductal hyperplasia (Peri-PM with ADH) and 60 DCIS. Normal breast tissues were selected as a control group. RESULTS Based on immunohistochemical staining, the positive rate of E2F-1 expression in Peri-PM, Peri-PM with ADH and DCIS was 21.7%, 46.7% and 78.3% respectively. The positive rate of Rb expression was 83.3 %, 53.9% and 21.7% and the ER expression was 86.7%,61.7% and 55.0%. Significant differences were found among the 3 groups (Peri-PM, Peri-PM with ADH and DCIS) (P<0.05). Significant differences existed between any 2 groups (P<0.05) except for the rate of ER positive expression comparing Peri-PM with ADH verus DCIS (P>0.05). The expression of E2F-1 was nega- tively correlated with ER and Rb, and at the same time the expression of ER was positively correlated with Rb. Following the degree of breast epithelial hyperplasia involved and its development into carcinoma, the positive rate of E2F-1 expression displayed an elevating tendency, but that of Rb and ER expression showed a tendency to decline. CONCLUSION The interaction of the 3 indexes studied may play an im- portant role in the conversion of precancerous lesions to early in situ breast carcinoma, and the evaluation of these indexes might provide a valuable basis for screening high-risk cases of Peri-PM.     

A vitamin D receptor-alkylating derivative of 1α,25-dihydroxyvitamin D3 inhibits growth of human kidney cancer cells and suppresses tumor growth

1,25-Dihydroxyvitamin D? [1,25(OH)?D?] has shown strong promise as an antiproliferative agent in several malignancies, yet its therapeutic use has been limited by its toxicity leading to search for analogues with antitumor property and low toxicity. In this study, we evaluated the in vitro and in vivo properties of 1,25-dihydroxyvitamin D?-3-bromoacetate [1,25(OH)?D?-3-BE], an alkylating derivative of 1,25(OH)?D?, as a potential therapeutic agent for renal cancer. Dose response of 1,25(OH)?D?-3-BE in 2 kidney cancer cell lines was evaluated for its antiproliferative and apoptotic properties, and mechanisms were evaluated by Western blot and FACS analyses. Therapeutic potential of 1,25(OH)?D?-3-BE was assessed both by determining its stability in human serum and by evaluating its efficacy in a mouse xenograft model of human renal tumor. We observed that 1,25(OH)?D?-3-BE is significantly more potent than an equivalent concentration of 1,25(OH)?D? in inhibiting growth of A498 and Caki 1 human kidney cancer cells. 1,25(OH)?D?-3-BE-mediated growth inhibition was promoted through inhibition of cell-cycle progression by downregulating cyclin A and induction of apoptosis by stimulating caspase activity. Moreover, 1,25(OH)?D?-3-BE strongly inhibited Akt phosphorylation and phosphorylation of its downstream target, caspase-9. 1,25(OH)?D?-3-BE seemed to be stable in human serum. In xenograft mouse model of human renal tumor, 1,25(OH)?D?-3-BE was more potent at reducing tumor size than 1,25(OH)?D?, which was accompanied by an increase in apopotosis and reduction of cyclin A staining in the tumors. These results suggest a translational potential of this compound as a therapeutic agent in renal cell carcinoma. Data from this study and extensive studies of vitamin D for the prevention of many malignancies support the potential of 1,25(OH)?D?-3-BE for preventing renal cancer and the development of relevant in vivo prevention models for assessing this potential, which do not exist at present.