ascorbic-acid and Endometrial-Neoplasms

Antioxidant vitamins may reduce cancer risk by limiting oxidative DNA damage. To summarize and quantify the current epidemiologic evidence of an association between antioxidant vitamin intake and endometrial cancer, we conducted a systematic literature review and meta-analysis. One cohort and 12 case-control studies presenting relevant risk estimates were identified by conducting bibliographical searches through June 2008. Dose-response meta-analyses were conducted for beta-carotene, vitamin C, and vitamin E from food sources. Intake from supplements was not considered in the meta-analyses because of the few studies that reported relevant information. Based on case-control data, the random-effects summary odds ratios (OR) were, for beta-carotene: 0.88 (95% CI: 0.79-0.98) per 1,000 mcg/1,000 kcal (I2: 77.7%; p < 0.01); for vitamin C: 0.85 (95% CI: 0.73-0.98) per 50 mg/1,000 kcal (I2: 66.1%; p < 0.01); and, for vitamin E: 0.91 (95% CI: 0.84-0.99) per 5 mg/1,000 kcal (I2: 0.0%; p: 0.45). In contrast, the only prospective study identified provided little indication of an association. Although the current case-control data suggest an inverse relationship of endometrial cancer risk with dietary intakes of beta-carotene, vitamin C, and vitamin E from food sources, additional studies are needed, particularly cohort studies, to confirm an association.

Topics: Adult; Antioxidants; Ascorbic Acid; beta Carotene; Case-Control Studies; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Vitamin E; Vitamins

Given the strong association between obesity and endometrial cancer risk, dietary factors may play an important role in the development of this cancer. However, observational studies of micro- and macronutrients and their role in endometrial cancer risk have been inconsistent. Clarifying these relationships are important to develop nutritional recommendations for cancer prevention. We performed two-sample Mendelian randomization (MR) to investigate the effects of circulating levels of 15 micronutrients (vitamin A (retinol), folate, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc) as well as corrected relative macronutrient intake (protein, carbohydrate, sugar and fat) on risks of endometrial cancer and its subtypes (endometrioid and non-endometrioid histologies). Genetically predicted vitamin C levels were found to be strongly associated with endometrial cancer risk. There was some evidence that genetically predicted relative intake of macronutrients (carbohydrate, sugar and fat) affects endometrial cancer risk. No other significant association were observed. Conclusions: In summary, these findings suggest that vitamin C and macronutrients influence endometrial cancer risk but further investigation is required.

Topics: Ascorbic Acid; Endometrial Neoplasms; Female; Humans; Mendelian Randomization Analysis; Risk Factors; Sugars; Vitamins

The aim of this study was to investigate peculiarities of ascorbic acid effect on radiation-induced chromosomal aberrations frequency and range in the cultured peripheral blood lymphocytes (PBL) of healthy donors and cancer patients depending on doses of radiation and drug, as well as cells radiosensitivity (in vitro).. Test system of human PBL, metaphase analysis of chromosomal aberrations. Cells were cultivated according to the standard procedures with some modifications. PBL culture was exposed to x-ray radiation in G0- and G2-phases of cell cycle. Immediately after the irradiation the culture was treated with ascorbic acid in concentrations of 20.0-80.0 µg/ml of blood.. Cell culture irradiation in low dose (0.3 Gy) and treatment with ascorbic acid in therapeutic concentration (20.0 μg/ml of blood) resulted in radioprotective effect, decreasing overall chromosome aberrations frequency as opposed to radiation effects. It has been established that post-irradiation effect of ascorbic acid upon the PBL culture in concentrations of 40.0 and 80.0 μg/ml, which exceeding therapeutic concentration value 2 and 4 times correspondingly, increased overall chromosome aberrations frequency 1.4 times compared with irradiation effect in a low dose (0.3 Gy). This bears evidence of ascorbic acid co-mutagenic activity in the range of concentrations exceeding therapeutic values. The peak of mitotic activity inhibition was observed at 2.0 Gy irradiation dose. Addition ascorbic acid in therapeutic concentration increased radiation effect this number ≈ 2 times (exceeding even intact control value). Compared with G0-phase, co-mutagenic effect of ascorbic acid in G2-phase appears earlier, starting with dose of 1.0 Gy. In the blood lymphocytes of cancer patients, the level of genetic damage was increased 1.7 times after combined treatment with low dose irradiation and ascorbic acid in comparison with irradiation alone which suggest the co-mutagenic instead of radioprotective effect of ascorbic acid.. Genome destabilization enhancement of irradiated in vitro human somatic cells under ascorbic acid effect is due to its co-mutagenic properties. The formation of co-mutagenic effects of ascorbic acid depend on its concentration, irradiation dose and the efficiency of repair processes. Co-mutagenes may pose high carcinogenic hazard at low (above background) radiation levels.

Topics: Ascorbic Acid; Case-Control Studies; Cell Cycle; Chromosome Aberrations; Dose-Response Relationship, Radiation; Endometrial Neoplasms; Female; Genome, Human; Genomic Instability; Humans; Lymphocytes; Mitotic Index; Radiation; Radiation Dosage; X-Rays

The objective of the present study was to determine the in-vitro effect of Abietyl-Isothiocyanate (ABITC), a representative of a new class of anti-cancer drugs, on endometrial cancer (EC) cell lines. ABITC at concentrations ≥1 μM displayed dose-dependent and selective cytotoxicity to EC cell lines (ECC-1, AN3CA, RL95-2) in comparison to other cancer cell lines. After treatment with ABITC, ECC-1 unlike control cells displayed hallmark features of apoptosis including chromatin condensation and nuclear fragmentation. At concentrations below the IC50, ABITC exerted anti-proliferative effects by blocking cell-cycle progression through G0/G1 and S-phase. In addition, cells attempted to counteract drug treatment by pro-survival signaling such as deactivation of JNK/SAPK and p38 MAPK and activation of AKT and ErK1/2. ABITC also altered EGF-receptor phosphorylation. At a concentration of 5 μM ABITC generated an excess amount of reactive oxygen species (ROS) and displayed pro-apoptotic signaling such as activation of caspase-8, JNK-SAPK and deactivation of PARP-1. Co-treatment with an antioxidant blocked the drug effects by reducing ROS generation, cytotoxicity and pro-apoptotic signaling. In summary, novel isothiocyanate ABITC is an anti-proliferative and selectively cytotoxic drug to EC cells in-vitro. Key mechanisms during cell death are predominantly correlated to excess generation of ROS. We suggest the further development of ABITC as a potential therapeutic by studying the drug efficacy in EC in-vivo models.

Topics: Abietanes; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Shape; Cell Survival; Drug Design; Endometrial Neoplasms; Female; Humans; Intracellular Space; Isothiocyanates; Reactive Oxygen Species; Signal Transduction

Activation of the transcription factor hypoxia-inducible factor (HIF)-1 allows solid tumors to thrive under conditions of metabolic stress. Because HIF-1 is switched off by hydroxylation reactions that require ascorbate, inadequate intracellular ascorbate levels could contribute to HIF-1 overactivation. In this study, we investigated whether the ascorbate content of human endometrial tumors [known to be driven by HIF-1 and vascular endothelial growth factor (VEGF)] influenced HIF-1 activity and tumor pathology. We measured protein levels of HIF-1alpha and three downstream gene products [glucose transporter 1 (GLUT-1), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and VEGF], as well as the ascorbate content of tumor and patient-matched normal endometrial tissue samples. HIF-1alpha and its downstream gene products were upregulated in tumor tissue, with the highest levels being present in high-grade tumors. High-grade tumors also had reduced capacity to accumulate ascorbate compared with normal tissue; however, all grades contained tumors with low ascorbate content. Tumors with the highest HIF-1alpha protein content were ascorbate deficient. Low ascorbate levels were also associated with elevated VEGF, GLUT-1, and BNIP3 protein levels and with increased tumor size, and there was a significant association between low tissue ascorbate levels and increased activation of the HIF-1 pathway (P = 0.007). In contrast, tumors with high ascorbate levels had lesser levels of HIF-1 activation. This study shows for the first time a likely in vivo relationship between ascorbate and HIF-1, with low tumor tissue ascorbate levels being associated with high HIF-1 activation and tumor growth.

Topics: Ascorbic Acid; Cell Count; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Membrane Proteins; Phenotype; Proto-Oncogene Proteins; Up-Regulation; Vascular Endothelial Growth Factor A

We have recently demonstrated that proteasome inhibitors can be effective in inducing apoptotic cell death in endometrial carcinoma cell lines and primary culture explants. Increasing evidence suggests that reactive oxygen species are responsible for proteasome inhibitor-induced cell killing. Antioxidants can thus block apoptosis (cell death) triggered by proteasome inhibition. Here, we have evaluated the effects of different antioxidants (edaravone and tiron) on endometrial carcinoma cells treated with aldehyde proteasome inhibitors (MG-132 or ALLN), the boronic acid-based proteasome inhibitor (bortezomib) and the epoxyketone, epoxomicin. We show that tiron specifically inhibited the cytotoxic effects of bortezomib, whereas edaravone inhibited cell death caused by aldehyde-based proteasome inhibitors. We have, however, found that edaravone completely inhibited accumulation of ubiquitin and proteasome activity decrease caused by MG-132 or ALLN, but not by bortezomib. Conversely, tiron inhibited the ubiquitin accumulation and proteasome activity decrease caused by bortezomib. These results suggest that edaravone and tiron rescue cells of proteasome inhibitors from cell death, by inhibiting blockade of proteasome caused by MG-132 and ALLN or bortezomib, respectively. We also tested other antioxidants, and we found that vitamin C inhibited bortezomib-induced cell death. Similar to tiron, vitamin C inhibited cell death by blocking the ability of bortezomib to inhibit the proteasome. Until now, all the antioxidants that blocked proteasome inhibitor-induced cell death also blocked the proteasome inhibitor mechanism of action.

Topics: Antioxidants; Antipyrine; Apoptosis; Ascorbic Acid; Blotting, Western; Boronic Acids; Bortezomib; Butylated Hydroxyanisole; Caspase 3; Caspase 9; Caspase Inhibitors; Cell Line, Tumor; Cell Survival; Coumarins; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Edaravone; Endometrial Neoplasms; Ergothioneine; Female; Humans; Leupeptins; Oligopeptides; Proteasome Inhibitors; Pyrazines; Ubiquitin; Vitamin E; Vitamins

Curative potential of riboflavin, niacin and ascorbic acid against tamoxifen mediated endometrial carcinoma was established by studies on carbohydrate metabolizing enzymes. The enzymes investigated were glycolytic enzymes namely, hexokinase; aldolase; phosphoglucoisomerase and the gluconeogenic enzymes namely, glucose-6-phosphatase and fructose-1, 6-biphosphatase in endometrial carcinoma bearing rats. A significant increase in glycolytic enzymes and a subsequent decrease in gluconeogenic enzymes were observed in plasma, liver and kidney of endometrial carcinoma animals. The administration of riboflavin (45 mg/kg bw/day), niacin (100 mg/kg bw/day) and ascorbic acid (200 mg/kg bw/day) along with tamoxifen (45 mg/kg bw/day) caused a significant decrease in the activity of glycolytic enzymes and a significant increase in the activities of gluconeogenic enzymes to near normal levels in experimental animals. Our results suggest that riboflavin, niacin and ascorbic acid have potential combination therapy against tamoxifen mediated secondary endometrial carcinoma in experimental rats. However, there were no deleterious side effects observed in combinants alone treated animals.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Carbohydrate Metabolism; Carcinoma; Drug Evaluation, Preclinical; Endometrial Neoplasms; Female; Neoplasm Metastasis; Niacin; Rats; Rats, Sprague-Dawley; Riboflavin; Tamoxifen

Telomerase activation can be considered as a critical step in cell immortalization. The enzyme elongates or maintains telomere length by adding to its end tandem TTAGGG repeats by using its endogenous RNA template. Telomerase is not detectable in most somatic cells but is upregulated in germ line cells and in 85-90% of human cancers, which suggests important role of telomerase in neoplastic transformation. Consequently, telomerase has been proposed as a potentially highly selective target for the development of antiproliferative agents. Platinum complexes are widely administrated in cancer therapy. A conjugate of selenite with diammineplatinum [(NH(3))(2)Pt(SeO(3))(2)] is a novel potential anticancer drug. Using alkaline single cell gel electrophoresis (comet assay), we showed that the drug at 5-30 microM induced concentration-dependent damage to DNA of endometrial cancer cells derived from tumor samples. Sodium ascorbate at 10 and 50 microM reduced the extent of the DNA damage evoked by the drug. (NH(3))(2)Pt(SeO(3)) reduced telomerase activity in the cells in a concentration-dependent manner as measured by using the telomere repeat amplification protocol (TRAP) assay. This effect was independent of sodium ascorbate. Therefore, mutagenic effects of the conjugate can be reduced by well-recognized antimutagen, sodium ascorbate, but it can still retain ability to affect neoplastic transformation. The results obtained indicate that (NH(3))(2)Pt(SeO(3)) may specifically inhibit telomerase activity in endometrial cancer cells.

Topics: Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cell Survival; Cell Transformation, Neoplastic; Cisplatin; Comet Assay; DNA Damage; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Polymerase Chain Reaction; Selenium Compounds; Telomerase; Telomere