ascorbic-acid and Pancreatic-Neoplasms

Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank-the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608-0.985,

Topics: Antioxidants; Ascorbic Acid; Colonic Neoplasms; Diet; Digestive System Neoplasms; Food; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; United Kingdom; Vitamin A

Observational studies inconsistently reported the relationship between vitamin C intake and risk of pancreatic cancer. We conducted a meta-analysis of published case-control and cohort studies to quantify the association.. Potentially eligible studies were found on PubMed and EMBASE databases through May 31, 2015. A random-effects model was assigned to compute summary point estimates with corresponding 95% confidence intervals (CIs). Subgroup and meta-regression analyses were also performed to explore sources of heterogeneity.. Our final analyses included 20 observational studies comprising nearly 5 thousand cases of pancreatic cancer. When comparing the highest with the lowest categories of vitamin C intake, the summary odds ratio/relative risk for case-control studies (14 studies), cohort studies (6 studies) and all studies combined was 0.58 (95% CI: 0.52-0.66), 0.93 (95% CI: 0.78-1.11) and 0.66 (95% CI: 0.58-0.75), respectively. The difference in the findings between case-control and cohort studies was statistically significant (P < .001). Possible publication bias was shown in the meta-analysis of case-control studies.. There is insufficient evidence to conclude any relationship between vitamin C intake and risk of pancreatic cancer. The strong inverse association observed in case-control studies may be affected by biases (eg, recall and selection biases) that particularly affect case-control studies and/or potential publication bias. Future prospective studies of vitamin C intake and pancreatic cancer are needed.

Topics: Antioxidants; Ascorbic Acid; Case-Control Studies; Cohort Studies; Humans; Pancreatic Neoplasms; Risk

We conducted a meta-analysis to systematically evaluate the association between antioxidants intake and pancreatic cancer risk. Relevant articles were retrieved from PUBMED and EMBASE databases and standard meta-analysis methods were applied. Finally a total of 18 studies were included. Comparing the highest with lowest categories, higher dietary intakes of selenium, vitamin C, vitamin E, β-carotene and β-cryptoxanthin were significantly associated with reduced pancreatic cancer risk (for selenium, pooled OR = 0.47, 95%CI 0.26-0.85; for vitamin C, pooled OR = 0.68, 95%CI 0.57-0.80; for vitamin E, pooled OR = 0.70, 95%CI 0.62-0.81; for β-carotene, pooled OR = 0.74, 95%CI 0.56-0.98; for β-cryptoxanthin, pooled OR = 0.70, 95%CI 0.56-0.88). Lycopene intake was marginally associated with pancreatic cancer risk (pooled OR = 0.85, 95%CI 0.73-1.00), while no significant association was observed for α-carotene, lutein and zeaxanthin. In summary, higher dietary intake of selenium, vitamin C, vitamin E, β-carotene and β-cryptoxanthin was inversely associated with pancreatic cancer risk.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Beta-Cryptoxanthin; Carotenoids; Databases, Factual; Diet; Humans; Lutein; Lycopene; Pancreatic Neoplasms; Risk Factors; Selenium; Vitamin E; Zeaxanthins

The prognosis for patients diagnosed with pancreatic cancer remains dismal, with less than 3% survival at 5 years. Recent studies have demonstrated that high-dose, intravenous pharmacological ascorbate (ascorbic acid, vitamin C) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells vs. normal cells, suggesting a promising new role of ascorbate as a therapeutic agent. At physiologic concentrations, ascorbate functions as a reducing agent and antioxidant. However, when pharmacological ascorbate is given intravenously, it is possible to achieve millimolar plasma concentration. At these pharmacological levels, and in the presence of catalytic metal ions, ascorbate can induce oxidative stress through the generation of hydrogen peroxide (H2O2). Recent in vitro and in vivo studies have demonstrated ascorbate oxidation occurs extracellularly, generating H2O2 flux into cells resulting in oxidative stress. Pharmacologic ascorbate also inhibits the growth of pancreatic tumor xenografts and displays synergistic cytotoxic effects when combined with gemcitabine in pancreatic cancer. Phase I trials of pharmacological ascorbate in pancreatic cancer patients have demonstrated safety and potential efficacy. In this chapter, we will review the mechanism of ascorbate-induced cytotoxicity, examine the use of pharmacological ascorbate in treatment and assess the current data supporting its potential as an adjuvant in pancreatic cancer.

Topics: Animals; Antioxidants; Ascorbic Acid; Deoxycytidine; Gemcitabine; Humans; Hydrogen Peroxide; Oxidative Stress; Pancreatic Neoplasms

Quantification of the association between the intake of vitamin C and risk of pancreatic cancer is still conflicting. We therefore conducted a meta-analysis to assess the association between them. Pertinent studies were identified by a search of PubMed and Web of Knowledge throughSeptember of 2014. A random effects model was used to combine the data for analysis. Sensitivity analysis and publication bias were conducted. Data from 17 studies including 4827 pancreatic cancer cases were used in this meta-analysis. Pooled results suggested that highest vitamin C intake amount versus lowest amount was significantlyassociated with reduced the risk of pancreatic cancer [summary relative risk (RR) = 0.705, 95% CI = 0.612-0.811, I(2) = 42.3%]. The associations were also significant both in Caucasian [summary RR = 0.741, 95% CI = 0.626-0.876], Asian [summary RR = 0.455, 95% CI = 0.275-0.754] and Mixed population [summary RR = 0.677, 95% CI = 0.508-0.901]. No publication bias was found. Our analysis suggested that the higher intake of vitamin C might reduce the risk of pancreatic cancer.

Topics: Ascorbic Acid; Diet; Humans; Pancreatic Neoplasms; Publication Bias; Risk

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer.

Topics: Adenocarcinoma; Apoptosis; Ascorbic Acid; Cell Proliferation; Combined Modality Therapy; Dietary Supplements; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Survival Rate; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

Epidemiologic evidence on the relation between nutrition and pancreatic cancer is reviewed. A number of epidemiologic studies of diet and cancer of the pancreas have been reported including descriptive, case-control, and cohort studies. Overall, fairly consistent patterns of positive associations with the intake of meat, carbohydrates, and dietary cholesterol have been observed. Consistent inverse relationships with fruit and vegetable intakes and, in particular, with two markers of such foods, namely fiber and vitamin C, also have been noted. However, the methodologic limitations of these studies, particularly the descriptive and case-control studies, are such that causal inferences regarding these empirical associations currently are not warranted. Future follow-up of existing dietary cohorts should enable more precise assessment of the possible role of diet in the etiology of cancer of the pancreas.

Topics: Animals; Ascorbic Acid; Case-Control Studies; Causality; Cholesterol, Dietary; Cohort Studies; Diet; Dietary Carbohydrates; Dietary Fiber; Follow-Up Studies; Fruit; Humans; Meat; Nutritional Physiological Phenomena; Pancreatic Neoplasms; Vegetables

Gastrointestinal cancers, mainly oesophageal, gastric, pancreatic and large bowel cancer, account for about 40,000 deaths annually in England and Wales which is 32% of all cancer deaths. Nutritional factors have been implicated in the cause of each cancer and probably act by promoting the effect of carcinogenic substances taken in the diet or produced in the gut. Gastric cancer for example may be due to nitrosamine production in the stomach. This is enhanced by readily available sources of dietary nitrite and nitrate whilst the reaction is inhibited by vitamin C and low temperatures (2 degrees C). By contrast large bowel cancer can be related to high fat and meat intakes whilst a protective role for dietary fibre has been suggested. Dietary factors in the aetiology of oesophageal cancer differ from one high incidence area to another.

Topics: Animals; Ascorbic Acid; Cold Temperature; Diet; Dietary Fats; Dietary Fiber; Digestive System; Esophageal Neoplasms; Gastrointestinal Motility; Gastrointestinal Neoplasms; Humans; Intestinal Neoplasms; Meat; Nitrosamines; Organ Specificity; Pancreatic Neoplasms; Stomach Neoplasms

Pharmacological ascorbate (P-AscH

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Female; Humans; Hydrogen Peroxide; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neoplastic Cells, Circulating; Pancreatic Neoplasms; Peroxides

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH

Topics: Aged; Aged, 80 and over; Animals; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Cell Survival; Collagen; Deoxycytidine; Disease-Free Survival; DNA Damage; Female; Gemcitabine; Glutathione; Humans; Male; Mice; Mice, Nude; Middle Aged; Oxidative Stress; Pancreatic Neoplasms; Radiation Tolerance; Radiotherapy; Recombinant Proteins; Treatment Outcome

Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate's anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ascorbic Acid; Cell Proliferation; Deoxycytidine; Female; Follow-Up Studies; Gemcitabine; Humans; Infusions, Parenteral; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Prognosis; Prospective Studies; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma.. Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored.. Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months.. Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Ascorbic Acid; Chromatography, High Pressure Liquid; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Gemcitabine; Glutathione; Humans; Infusions, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Patient Compliance; Patient Safety; Sentinel Lymph Node Biopsy

Oxidative stress due to ischemia/reperfusion injury increases systemic inflammation and impairs immune defenses. Much interest has developed for the administration of antioxidant substrates in surgical patients. The purpose of this study was to perform a pilot evaluation of the impact of a carbohydrate- containing preconditioning oral nutritional supplement (pONS) enriched with glutamine, antioxidants, and green tea extract on postoperative oxidative stress.. We performed a double-blind placebo-controlled randomized clinical trial, involving 36 cancer patients undergoing pancreaticoduodenectomy. Patients were randomized to receive either pONS or placebo twice the day before surgery and once 3 hours before surgery. Total endogenous antioxidant capacity (TEAC), plasma levels of vitamin C, vitamin E, selenium, zinc, F2-isoprostanes, and C-reactive protein were measured at baseline and on postoperative day (POD) 1, 3, and 7.. At surgery, the mean gastric residual volume (mL) was 54.2 in the pONS group versus 51.3 in the placebo group (P = NS). On POD 1 plasma levels of vitamin C (P = 0.001), selenium (P = 0.07), and zinc (P = 0.06) were higher in the pONS group compared to placebo. TEAC was improved on POD 1, 3, and 7 in the pONS group compared to placebo (P = 0.01). No difference was found in plasma C-reactive protein levels after surgery in both groups.. Perioperative pONS administration positively affected plasma vitamin C levels and improved TEAC shortly after surgery, but did not reduce oxidative stress and systemic inflammation markers.

Topics: Aged; Antioxidants; Ascorbic Acid; Common Bile Duct Neoplasms; Dietary Supplements; Double-Blind Method; Humans; Male; Middle Aged; Oxidative Stress; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pilot Projects; Postoperative Complications; Preoperative Care; Reperfusion Injury; Selenium; Zinc

Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.. 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.. These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.. Clinicaltrials.gov NCT00954525.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Erlotinib Hydrochloride; Female; Gemcitabine; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pancreatic Neoplasms; Pulmonary Embolism; Quinazolines; Treatment Outcome

Case-control studies of pancreatic cancer were conducted in 5 populations with moderate to high rates and differing dietary practices, using a common protocol and questionnaire. Comprehensive diet histories were completed for a total of 802 cases and 1669 controls identified in Adelaide (Australia), Montreal and Toronto (Canada), Utrecht (The Netherlands) and Opole (Poland). Positive associations were observed with intake of carbohydrates and cholesterol, and inverse associations with dietary fiber and vitamin C. These relationships were generally consistent among the 5 studies, and showed statistically significant and generally monotonic dose-response relationships. The relative risks for highest vs. lowest quintile of intake were estimated for carbohydrates to be 2.57 (95% confidence interval 1.64-4.03), cholesterol 2.68 (1.72-4.17), dietary fiber 0.45 (0.30-0.63), and vitamin C 0.53 (0.38-0.76). The consistency, strength, and specificity of these associations provides evidence for the hypothesis that some or all of these dietary factors may alter the risk of pancreatic cancer.

Topics: Adult; Aged; Ascorbic Acid; Australia; beta Carotene; Body Height; Body Weight; Canada; Carotenoids; Case-Control Studies; Cholesterol, Dietary; Diet; Dietary Fiber; Energy Intake; Feeding Behavior; Female; Humans; Male; Middle Aged; Netherlands; Pancreatic Neoplasms; Poland; Vitamin A

Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH. Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH. KU60019 with P-AscH. We provide evidence that redox modulating drugs, such as P-AscH

Topics: Animals; Ascorbic Acid; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line, Tumor; DNA Damage; Humans; Hydrogen Peroxide; Mice; Oxidation-Reduction; Pancreatic Neoplasms; Therapeutic Index

Pancreatic cancer (PC) shows a very poor response to current treatments. Development of drug resistance is one of the causes of the therapy failure, being PARP1 (poly ADP-ribose polymerase 1) a relevant protein in the resistance mechanism. In this work, we have functionalized calcium phosphate-based nanoparticles (NPs) with Olaparib (OLA, a PARP-1 inhibitor) in combination with ascorbic acid (AA), a pro-oxidative agent, to enhance their individual effects.. Amorphous Calcium Phosphate (ACP) NPs were synthesized through a biomimetic approach and then functionalized with OLA and AA (NP-ACP-OLA-AA). After evaluation of the loading capacity and release kinetic, cytotoxicity, cell migration, immunofluorescence, and gene expression assays were performed using pancreatic tumor cell lines. In vivo studies were carried out on tumors derived from the PANC-1 line in NOD SCID gamma (NSG) mice.. NP-ACP-OLA-AA was loaded with 13%wt of OLA (75% loading efficiency) and 1% of AA, respectively. The resulting dual nanosystem exhibited a gradual release of OLA and AA, being the latter protected from degradation in solution. This ensured the simultaneous availability of OLA and AA for a longer period, at least, during the entire time of in vitro cell experiments (72 hours). In vitro studies indicated that NP-ACP-OLA-AA showed the best cytotoxic effect outperforming that of the free OLA and a higher genotoxicity and apoptosis-mediated cytotoxic effect in human pancreatic ductal adenocarcinoma cell line. Interestingly, the in vivo assays using immunosuppressed mice with PANC-1-induced tumors revealed that NP-ACP-OLA-AA produced a higher tumor volume reduction (59.1%) compared to free OLA (28.3%) and increased the mice survival.. Calcium phosphate NPs, a highly biocompatible and biodegradable system, were an ideal vector for the OLA and AA co-treatment in PC, inducing significant therapeutic benefits relative to free OLA, including cytotoxicity, induction of apoptosis, inhibition of cell migration, tumor growth, and survival.

Topics: Animals; Ascorbic Acid; Humans; Mice; Mice, SCID; Pancreatic Neoplasms

Di-(2-ethylhexyl)-phthalate (DEHP), a common Phthalic acid ester (PAEs), has been reported to be associated with diabetes mellitus, yet the underlying mechanisms remain unknown. Combined nutrient interventions have been shown to alleviate the diabetic toxicity of DEHP. However, the effects and mechanisms of the combined intervention of Astragalus and vitamins (C and E) are currently unknown. In this study, we investigated the potential mechanisms of DEHP-induced diabetes mellitus through transcriptome analysis and vitro experiments using rat insulinoma cells (INS-1 cells). Furthermore, we explored the protection of the combined Astragalus, vitamin C, and vitamin E on DEHP-induced diabetes mellitus through these mechanisms. INS-1 cells in the logarithmic growth period were exposed to 125 umol/L DEHP followed by high-throughput sequencing analysis. The cell proliferation inhibition rate was determined using MTT assay for each group, and the cell apoptosis rate and intracellular ROS level were measured using flow cytometer. Finally, insulin levels and markers of oxidative stress were detected using ELISA kits in different groups. A total of 372 differentially expressed genes were found between the 125 umol/L DEHP and control groups, subsequent functional enrichment analyses indicated that DEHP induced oxidative stress and disturbed insulin levels. In INS-1 cells, the rate of cell proliferation inhibition, apoptosis, and the degree of oxidative stress increased concentration-dependently with increasing DEHP concentrations, while antioxidant intervention could reverse these changes. Insulin synthesis and secretion decreased after 240 μmol/L DEHP exposure stimulated by 25 mM glucose in INS-1 cells, also could antioxidant intervention alleviate these reductions. Based on these results, the underlying mechanism of DEHP impairing the function of INS-1 cells might be through apoptosis pathways induced by oxidative stress and direct reduction of insulin levels (both synthesis and secretion), while the optimal combination of Astragalus and vitamins (C and E) could exert an alleviating effect.

Topics: Animals; Antioxidants; Ascorbic Acid; Diabetes Mellitus; Diethylhexyl Phthalate; Insulin; Insulinoma; Oxidative Stress; Pancreatic Neoplasms; Rats; Vitamin E; Vitamins

Topics: AMP-Activated Protein Kinases; Ascorbic Acid; Ferroptosis; Glutathione; Heme Oxygenase-1; Humans; Iron; NF-E2-Related Factor 2; Nuclear Respiratory Factor 1; Pancreatic Neoplasms; Piperazines

Pharmacological ascorbate (P-AscH - , high-dose, intravenous vitamin C) has shown promise as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) treatment. The objective of this study was to determine the effects of P-AscH - when combined with PDAC chemotherapies.. Clonogenic survival, combination indices, and DNA damage were determined in human PDAC cell lines treated with P-AscH - in combination with 5-fluorouracil, paclitaxel, or FOLFIRINOX (combination of leucovorin, 5-fluorouracil, irinotecan, oxaliplatin). Tumor volume changes, overall survival, blood analysis, and plasma ascorbate concentration were determined in vivo in mice treated with P-AscH - with or without FOLFIRINOX.. P-AscH - combined with 5-fluorouracil, paclitaxel, or FOLFIRINOX significantly reduced clonogenic survival in vitro. The DNA damage, measured by γH2AX protein expression, was increased after treatment with P-AscH - , FOLFIRINOX, and their combination. In vivo, tumor growth rate was significantly reduced by P-AscH - , FOLFIRINOX, and their combination. Overall survival was significantly increased by the combination of P-AscH - and FOLFIRINOX. Treatment with P-AscH - increased red blood cell and hemoglobin values but had no effect on white blood cell counts. Plasma ascorbate concentrations were significantly elevated in mice treated with P-AscH - with or without FOLFIRINOX.. The addition of P-AscH - to standard of care chemotherapy has the potential to be an effective adjuvant for PDAC treatment.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Mice; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer.

Topics: Ascorbic Acid; beta Catenin; Carcinogenesis; Carcinoma, Pancreatic Ductal; Caspases; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Glucose; Humans; Pancreatic Neoplasms; Wnt Signaling Pathway

Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment.. To determine how effective is the ATO/D-VC combination in suppression of PDAC the mouse transgenic model. This study investigated the antitumour effect of a novel combination of arsenic trioxide (ATO) and D-ascorbic acid isomer (D-VC). Such a combination can be used to treat KRAS mutant cancer by inducing catastrophic oxidative stress.. In this study, we examined the effectiveness of ATO and D-VC on xenograft models-AK192 cells transplanted into mice. Previously, it has been shown that a high concentration of Vitamin C (VC) selectively can kill the cells expressing KRAS.. The results of this study demonstrated that the combination of VC with a low dose of the oxidizing drug ATO led to the enhancement of the therapeutic effect. These findings suggest that the combined treatment using ATO and D-VC is a promising approach to overcome the limitation of drug selectivity and efficacy.

Topics: Animals; Arsenic Trioxide; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; Drug Combinations; Humans; Mice; Oxidation-Reduction; Oxidative Stress; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by advanced disease stage at presentation, aggressive disease biology, and resistance to therapy, resulting in an extremely poor 5-year survival rate of <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression, but exactly why is unclear and is hindered by the technical limitations of analyzing clinical samples.. We performed genome-wide epigenetic mapping of DNA modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmc) using oxidative bisulfite sequencing from formalin-embedded sections. We identified overlap with transcriptional signatures in formalin-fixed, paraffin-embedded tissue from resected patients, via bioinformatics using iCluster and mutational profiling and confirmed them in vivo.. We found that aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci, including GATA6, which promote differentiated classical pancreatic subtypes. We showed that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5-methylcytosine hydroxylase TET2. Furthermore, we found that SMAD4 directly supports TET2 levels in classical pancreatic tumors, and loss of SMAD4 expression was associated with reduced 5hmc, GATA6, and squamous-like tumors. Importantly, enhancing TET2 stability using metformin and vitamin C/ascorbic acid restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo.. We identified epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data showed that restoring epigenetic control increases biomarkers of classical pancreatic tumors that are associated with improved therapeutic responses and survival.

Topics: 5-Methylcytosine; Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Differentiation; Cell Line, Tumor; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Epigenome; Epigenomics; GATA6 Transcription Factor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Metformin; Mice, Nude; Mice, Transgenic; Pancreatic Neoplasms; Retrospective Studies; Smad4 Protein; Transcription, Genetic; Transcriptome; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Pharmacologic ascorbate treatment (P-AscH

Topics: Administration, Intravenous; Animals; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Down-Regulation; Dual Oxidases; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide; Mice; Oxidative Stress; Oxygen; Oxygen Consumption; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Reactive Oxygen Species; Up-Regulation; Xenograft Model Antitumor Assays

Epigenetic dysregulations are closely associated with the development of pancreatic ductal adenocarcinoma (PDAC), which is one of the most aggressive malignancies and currently has limited treatment options. Vitamin C (VC), an epigenetic mediator, exerts antitumor effects on several types of cancer. However, the clinical application of VC is limited, particularly in PDAC. Thus, to investigate the antitumor effects and explore the potential clinical application of VC in PDAC, the survival of patients from The Cancer Genome Atlas database were analyzed, and proliferation, apoptosis and migration assays were performed in the present study. It was first established that high expression levels of the sodium‑dependent VC transporter 2, a critical VC transporter, predicted a good prognosis in patients with pancreatic adenocarcinoma. It was further confirmed that VC directly inhibited proliferation, induced apoptosis and suppressed migration of human pancreatic cancer cells. Global 5‑hydroxymethylcytosine (5hmC) content was significantly upregulated in pancreatic cancer cells following VC treatment, predominantly relying on ten‑eleven translocation 2. Furthermore, VC could specifically increase 5hmC levels at the promotor region on PH domain leucine‑rich repeat protein phosphatase 2 (PHLPP2) and enhance PHLPP2 expression levels. When PHLPP2 expression levels were knocked down, VC was able to partially overcome the inhibition of pancreatic cancer cells. These results illustrated a novel and precise mechanism of action of epigenetic alterations that underly the inhibition of VC in pancreatic cancer, and emphasized that PHLPP2 may be a new biomarker and epigenetic target for the clinical treatment of VC in PDAC.

Topics: 5-Methylcytosine; Ascorbic Acid; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Pancreatic Neoplasms; Phosphoprotein Phosphatases; Prognosis; Promoter Regions, Genetic; Sodium-Coupled Vitamin C Transporters; Survival Analysis; Up-Regulation

Previous studies reported the inevitable destructive effects of radiotherapy on normal adjacent cells. Ascorbic Acid (AA) has been proposed as an effective anti-cancer agent with no obvious effects on normal cells.. The effects of Ascorbic acid in combination with radiotherapy on human pancreatic carcinoma cell line were studied.. The human pancreatic cancer cells were cultured and divided into four groups: control group (A) without any treatment, group B that received 2Gy radiotherapy alone, group C that was treated with 4mM AA alone, and group D that was co-treated with AA and radiotherapy. Cell viability, DNA fragmentation, expression of apoptotic genes, and Reactive Oxygen Species (ROS) production were determined in treated cells.. There was a noticeable decrease in cell viability after treatment with AA (and/or) radiotherapy. All treated groups showed elevated ROS production, Bax/Bcl2 expression, DNA fragmentation, and cytotoxycity compared with the control group. Cells under combination therapy showed the most cytotoxicity.. The results suggest that AA at a dose of 4mmol/l may be used as an effective radio-sensitizing agent in pancreatic cancer cell line.

Topics: Antineoplastic Agents; Ascorbic Acid; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pancreatic Neoplasms; Radiation Dosage; Reactive Oxygen Species; Structure-Activity Relationship; Tumor Cells, Cultured; X-Rays

Pharmacologic ascorbate (P-AscH

Topics: Animals; Ascorbic Acid; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Electron Spin Resonance Spectroscopy; Humans; Metalloporphyrins; Oxidation-Reduction; Pancreatic Neoplasms; Radiation-Sensitizing Agents

Ascorbate administered intravenously gives a high plasma concentration of this drug. Clinical trials with pancreatic carcinoma patients revealed their prolonged survival if treated with intravenous ascorbate. On the other hand, high plasma ascorbate concentration leads to severe side effects, such as nephrotoxicity. In the present paper, we advocate to lower intravenous ascorbate dosage along with monothiol N-acetylcysteine pretreatment due to anticipation of the same therapeutic effect but less or none of side effects. We describe in detail molecular mechanism of ascorbate action to be potentiated by N-acetylcysteine, as observed under in vitro conditions. Providing further arguments, we believe that the same mechanism may be employed in vivo.

Topics: Acetylcysteine; Administration, Intravenous; Antioxidants; Ascorbic Acid; Copper; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Hyaluronic Acid; Immune System; Kidney; Neoplasms; Pancreatic Neoplasms; Sulfhydryl Compounds

Pancreatic carcinoma is one of the most aggressive cancers overcoming chemoresistance. Thus, novel compounds to complement the current antitumor agents are in need. Ocoxin oral solution (OOS) has proven antioxidant, anti-inflammatory, and antistromagenic properties. The aim of this study was to analyze the effect of OOS in an experimental pancreatic cancer model and its implication in stroma-related chemoresistance to paclitaxel and gemcitabine.. Murine pancreatic carcinoma 266-6 cells were treated with OOS to analyze cell cycle and to perform a mRNA comparative microarray study. Then the viability was assessed in combination with paclitaxel and/or gemcitabine. Chemoresistance induced by the medium taken from fibroblast cultures was also investigated on 6 human pancreatic carcinoma cell lines. Furthermore, an experimental model of pancreatic cancer was carried out to study the effect of OOS in vivo.. Ocoxin oral solution enhances the cytotoxic effect of paclitaxel and gemcitabine, while it ameliorates the chemoresistance induced by fibroblast-derived soluble factors in human pancreatic cancer cells. The OOS also promotes the regulation of the expression of genes that are altered in pancreatic carcinoma and slows down 266-6 cell pancreatic tumor development in vivo.. Ocoxin oral solution could be a potential complement to the chemotherapeutic drugs for pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Ascorbic Acid; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Survival; Deoxycytidine; Drug Resistance, Neoplasm; Folic Acid; Gemcitabine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred C57BL; Neoplasms, Experimental; Paclitaxel; Pancreatic Neoplasms; Pantothenic Acid; Plant Extracts; Solutions; Vitamin B 12; Vitamin B 6; Zinc Sulfate

Previous studies have found that meat-derived mutagens increase, and vitamin C or E decrease, the risk of pancreatic cancer.. The aim of this study was to determine whether intake of vitamin C or E modulates the association between meat-derived mutagen exposure and risk of pancreatic cancer.. We conducted a case-control study in 1321 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 1061 healthy controls (aged 28-88 y). Cases and controls were frequency-matched by age, sex, and race/ethnicity. Mutagen intake was assessed using a meat preparation questionnaire. Intakes of vitamin C, E, and other dietary components were assessed via a food-frequency questionnaire in a subset of 811 cases and 818 controls. ORs and 95% CIs were estimated in multivariable-adjusted logistic regression models.. The risk of PDAC was not associated with meat intake but was associated with consumption of well-done grilled or barbecued chicken (OR: 1.57; 95% CI: 1.18, 2.09; P = 0.001). Intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was associated with increased PDAC risk (Ptrend = 0.047). Participants in the highest, as compared with the lowest, quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (PhIP) intake experienced a 38% increased risk of PDAC (95% CI: 1.00, 1.90; P = 0.048). Intakes of total vitamin C or E from food and supplements or from supplements alone were each inversely associated with PDAC risk. Stratified analyses showed differential associations for PhIP intake and PDAC risk, such that risk increased among individuals with lower intake of vitamin C or E and decreased among those with higher vitamin intake. Significant interactions of dietary vitamin C, dietary vitamin E, and total vitamin E with PhIP intake were detected (Pinteraction = 0.023, <0.001, and 0.013, respectively).. Consistent with experimental evidence, this study of 811 cases and 818 controls has shown that high intake of dietary vitamin C or E mitigates the risk of PhIP-related PDAC.

Topics: Aged; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Case-Control Studies; Dietary Exposure; Female; Humans; Male; Meat; Middle Aged; Mutagens; Pancreatic Neoplasms; Risk Factors; Vitamin E

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH

Topics: Adenocarcinoma; Animals; Ascorbic Acid; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Progression; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Prolyl Hydroxylases; Protein Processing, Post-Translational; Vascular Endothelial Growth Factor A

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is often discovered at an advanced stage with few therapeutic options. Current conventional regimens for PDA are associated with significant morbidity, decreased quality of life, and a considerable financial burden. As a result, some patients turn to integrative medicine therapies as an alternate option after a diagnosis of PDA. Intravenous pharmacologic ascorbic acid (PAA) is one such treatment. The use of PAA has been passionately debated for many years, but more recent rigorous scientific research has shown that there are significant blood concentration differences when ascorbic acid is given parenterally when compared to oral dosing. This pharmacologic difference appears to be critical for its role in oncology. Here, we report the use of PAA in a patient with poorly differentiated stage IV PDA as an exclusive chemotherapeutic regimen. The patient survived nearly 4 years after diagnosis, with PAA as his sole treatment, and he achieved objective regression of his disease. He died from sepsis and organ failure from a bowel perforation event. This case illustrates the possibility of PAA to effectively control tumor progression and serve as an adjunct to standard of care PDA chemotherapy regimens. Our patient's experience with PAA should be taken into consideration, along with previous research in cell, animal, and clinical experiments to design future treatment trials.

Topics: Administration, Intravenous; Aged; Ascorbic Acid; Biliary Tract Surgical Procedures; Carcinoma, Pancreatic Ductal; Disease Progression; Humans; Integrative Medicine; Male; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Prognosis; Stents

Pharmacological ascorbate (AscH(-)) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells compared with normal cells. Positron emission tomography (PET) with the thymidine analog 3'-deoxy-3'-((18)F) fluorothymidine (FLT) enables noninvasive imaging and quantification of the proliferation fraction of tumors. We hypothesized that the rate of tumor proliferation determined by FLT-PET imaging, would be inversely proportional to tumor susceptibility to pharmacological AscH(-)-based treatments. Indeed, there was decreased FLT uptake in human pancreatic cancer cells treated with AscH(-) in vitro, and this effect was abrogated by co-treatment with catalase. In separate experiments, cells were treated with AscH(-), ionizing radiation or a combination of both. These studies demonstrated that combined AscH(-) and radiation treatment resulted in a significant decrease in FLT uptake that directly correlated with decreased clonogenic survival. MicroPET (18)F-FLT scans of mice with pre-established tumors demonstrated that AscH(-) treatment induced radiosensitization compared to radiation treatment alone. These data support testing of pharmacological ascorbate as a radiosensitizer in pancreatic cancer as well as the use of FLT-PET to monitor response to therapy.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Chemoradiotherapy; Dideoxynucleosides; Drug Monitoring; Humans; Isotope Labeling; Metabolic Clearance Rate; Mice; Mice, Nude; Pancreatic Neoplasms; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiopharmaceuticals; Radiotherapy Dosage; Treatment Outcome

Ascorbate (AscH

Topics: A549 Cells; Animals; Antioxidants; Ascorbic Acid; Catalase; Cell Line, Tumor; Hep G2 Cells; Humans; Hydrogen Peroxide; Mice; Oxidative Stress; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

Evidence of a protective effect of several antioxidants and other nutrients on pancreatic cancer risk is inconsistent. The aim of this study was to investigate the association for prediagnostic plasma levels of carotenoids, vitamin C, retinol and tocopherols with risk of pancreatic cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). 446 incident exocrine pancreatic cancer cases were matched to 446 controls by age at blood collection, study center, sex, date and time of blood collection, fasting status and hormone use. Plasma carotenoids (α- and β-carotene, lycopene, β-cryptoxanthin, canthaxanthin, zeaxanthin and lutein), α- and γ-tocopherol and retinol were measured by reverse phase high-performance liquid chromatography and plasma vitamin C by a colorimetric assay. Incidence rate ratios (IRRs) with 95% confidence intervals (95%CIs) for pancreatic cancer risk were estimated using a conditional logistic regression analysis, adjusted for smoking status, smoking duration and intensity, waist circumference, cotinine levels and diabetes status. Inverse associations with pancreatic cancer risk were found for plasma β-carotene (IRR highest vs. lowest quartile 0.52, 95%CI 0.31-0.88, p for trend = 0.02), zeaxanthin (IRR highest vs. lowest quartile 0.53, 95%CI 0.30-0.94, p for trend = 0.06) and α-tocopherol (IRR highest vs. lowest quartile 0.62, 95%CI 0.39-0.99, p for trend = 0.08. For α- and β-carotene, lutein, sum of carotenoids and γ-tocopherol, heterogeneity between geographical regions was observed. In conclusion, our results show that higher plasma concentrations of β-carotene, zeaxanthin and α-tocopherol may be inversely associated with risk of pancreatic cancer, but further studies are warranted.

Topics: Adult; Aged; Ascorbic Acid; Carotenoids; Case-Control Studies; Female; Humans; Male; Micronutrients; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Risk; Tocopherols; Vitamin A

Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(•-), an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Ascorbic Acid; Catalase; Catalysis; Deoxycytidine; Drug Synergism; Fluorescent Antibody Technique; Free Radical Scavengers; Gemcitabine; Histones; Humans; Hydrogen Peroxide; Metalloporphyrins; Mice; Mice, Nude; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Line; Cell Line, Tumor; Cell Survival; Chemoradiotherapy; DNA Damage; Dose-Response Relationship, Radiation; Glutathione; Glutathione Disulfide; Humans; Hydrogen Peroxide; Kaplan-Meier Estimate; Linear Models; Mice, Nude; Oxidative Stress; Pancreatic Neoplasms; Radiation-Sensitizing Agents; Radiation, Ionizing; Tumor Burden; Xenograft Model Antitumor Assays

The present study investigates the anticancer effect of ascorbate in MIA-PaCa-2 human pancreatic cancer cells using both in vitro and in vivo models, with a focus on assessing the role of oxidative stress and autophagy as important mechanistic elements in its anticancer actions. We showed that ascorbate suppresses the growth of human pancreatic cancer cells via the induction of oxidative stress and caspase-independent cell death. Ascorbate induces the formation of autophagosomes and the presence of autophagy inhibitors suppresses ascorbate-induced cell death. These data suggest that the induction of autophagosome formation contributes to ascorbate-induced pancreatic cancer cell death.

Topics: Animals; Antineoplastic Agents; Apoptosis Regulatory Proteins; Ascorbic Acid; Autophagy; Beclin-1; Cell Death; Cell Line, Tumor; Female; Humans; Membrane Proteins; Mice, Nude; Microtubule-Associated Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; RNA, Small Interfering; Xenograft Model Antitumor Assays

Topics: Ascorbic Acid; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Fatal Outcome; Female; Humans; Infusions, Intravenous; Middle Aged; Naturopathy; Neuroendocrine Tumors; Pancreatic Neoplasms; Vitamins

Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.

Topics: Animals; Ascorbic Acid; Catalase; Catalysis; Cell Line, Tumor; Humans; Hydrogen Peroxide; Manganese; Metalloporphyrins; Mice; Mice, Nude; Oxidation-Reduction; Oxygen Consumption; Pancreatic Neoplasms; Superoxide Dismutase; Xenograft Model Antitumor Assays

The objective was to examine the inhibitory effects of citrus fruit bioactive compounds on BxPC-3 and PANC-1 human pancreatic cancer cells, focusing on the antiproliferative mechanism of action of the flavonoid apigenin related to the glycogen synthase kinase-3β/nuclear factor kappa B signaling pathway.. Flavonoids, limonoids, phenolic acids, and ascorbic acid were tested for cytotoxic effects on BxPC-3 and PANC-1 cells; apigenin was the most potent (IC50 = 23 and 12 μM for 24 and 48 h for BxPC-3 and IC50 = 71 and 41 μM for 24 and 48 h for PANC-1). Apigenin induced pancreatic cell death through inhibition of the glycogen synthase kinase-3β/nuclear factor kappa B signaling pathway. Apigenin arrested cell cycle at G2 /M phase (36 and 32% at 50 μM for BxPC-3 and PANC-1, respectively) with concomitant decrease in the expression of cyclin B1. Apigenin activated the mitochondrial pathway of apoptosis (44 and 14% at 50 μM for BxPC-3 and PANC-1, respectively) and modified the expression of apoptotic proteins. Apigenin highly upregulated the expression of cytokine genes IL17F (114.2-fold), LTA (33.1-fold), IL17C (23.2-fold), IL17A (11.3-fold), and IFNB1 (8.9-fold) in BxPC-3 cells, which potentially contributed to the anticancer properties.. Flavonoids have a protective role in pancreatic cancer tumorigenesis.

Topics: Antineoplastic Agents, Phytogenic; Apigenin; Apoptosis; Ascorbic Acid; Catalytic Domain; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Citrus; Cytokines; Drug Screening Assays, Antitumor; Flavonoids; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Inflammation; NF-kappa B; Pancreatic Neoplasms; Signal Transduction

Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA). AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,4'-diisothiocyanatostilbene-2, 2' disulfonic acid), the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 62% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosis was shifted to VDAC-mediated "targeted" aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, also known as targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Cell Line, Tumor; Disease Models, Animal; Disulfiram; Dose-Response Relationship, Drug; Heterografts; Humans; Male; Mice; Necrosis; Oxides; Pancreatic Neoplasms; Reactive Oxygen Species; Tumor Stem Cell Assay; Voltage-Dependent Anion Channels

Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (MIA PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors.

Topics: Animals; Ascorbic Acid; Cell Line, Tumor; Ferritins; Humans; Iron; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Prostate; Radiation, Ionizing; Transplantation, Heterologous

To investigate whether the dietary antioxidants vitamins C and E, selenium and zinc decrease the risk of developing pancreatic cancer, for the first time using 7-day food diaries, the most accurate dietary methodology in prospective work.. 23,658 participants, aged 40-74 years, recruited into the EPIC-Norfolk Study completed 7-day food diaries which recorded foods, brands and portion sizes. Nutrient intakes were calculated in those later diagnosed with pancreatic cancer and in 3970 controls, using a computer program with information on 11,000 foods. Vitamin C was measured in serum samples. The HRs of developing pancreatic cancer were estimated across quartiles of intake and thresholds of the lowest quartile (Q1) against a summation of the three highest (Q2-4).. Within 10 years, 49 participants (55% men), developed pancreatic cancer. Those eating a combination of the highest three quartiles of all of vitamins C and E and selenium had a decreased risk (HR=0.33, 95% CI 0.13 to 0.84, p<0.05). There were threshold effects (Q2-4 vs Q1) for selenium (HR=0.49, 95% CI 0.26 to 0.93, p<0.05) and vitamin E (HR=0.57, 95% CI 0.29 to 1.09, p<0.10). The HRs of quartiles for antioxidants, apart from zinc, were <1, but not statistically significant. For vitamin C, there was an inverse association with serum measurements (HR trend=0.67, 95% CI 0.49 to 0.91, p=0.01), but the threshold effect from diaries was not significant (HR=0.68, 95% CI 0.37 to 1.26).. The results support measuring antioxidants in studies investigating the aetiology of pancreatic cancer. If the association is causal, 1 in 12 cancers might be prevented by avoiding the lowest intakes.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Biomarkers; Cohort Studies; Diet; Diet Records; England; Feeding Behavior; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Risk Factors; Selenium; Vitamin E; Zinc

Epidemiological data investigating the relation between fruit and vegetable consumption and pancreatic cancer risk have shown inconsistent results so far. Most case-control studies observed an inverse association with total fruit and vegetable consumption, whereas results from most cohort studies have largely been null. We examined prospectively the relation between pancreatic cancer risk and intake of vegetables, fruits, carotenoids and vitamins C and E. The Netherlands Cohort Study consisted of 120,852 men and women who completed a questionnaire at baseline in 1986, including a validated 150-item food-frequency questionnaire. After 16.3 years of follow-up, 423 cases were available for analysis. Total vegetable and total fruit consumption were not associated with pancreatic cancer risk (highest vs. lowest quintile, multivariable-adjusted hazard rate ratio = 1.23, 95% confidence interval: 0.86-1.75 and multivariable-adjusted hazard rate ratio = 0.90, 95% confidence interval: 0.66-1.24, respectively). Also, for cooked vegetables, raw vegetables and vegetables and fruits classified into subgroups, no associations were observed. Dietary carotenoids, vitamin C and E intake and supplements containing vitamin C or E were not associated with pancreatic cancer risk. The results were not modified by sex, smoking status and body mass index. In conclusion, we observed no association between a high consumption of vegetables and fruits and pancreatic cancer risk in this large cohort study, which is in agreement with previous prospective studies. Furthermore, we observed no association between the intake of carotenoids, vitamins and vitamin supplements and pancreatic cancer risk.

Topics: Ascorbic Acid; Carotenoids; Case-Control Studies; Cohort Studies; Diet Records; Dietary Supplements; Female; Follow-Up Studies; Fruit; Health Surveys; Humans; Male; Middle Aged; Netherlands; Pancreatic Neoplasms; Prognosis; Prospective Studies; Risk Factors; Surveys and Questionnaires; Vegetables; Vitamin E; Vitamins

The molecular basis of interaction of selected carotenoids and xanthophylls with ascorbic acid on cancer cells was studied to determine their anticancer effects.. Drug accumulation was measured in a human ABCB1 gene-transfected mouse lymphoma cell line and in a human lung cancer cell line by flow cytometry; furthermore, their anticancer effects were determined in mice in vivo.. Several carotenoids inhibited the multidrug resistance of cancer cells. Ascorbic acid improved the effect of certain xanthophylls, but the effect of capsanthin was not modified. Capsanthin had weak (12%) but capsorubin (85%) had a remarkable antiproliferative effect on A549 lung cancer cells. Capsorubin reduced immediate-early tumor antigen expression, while capsanthin was not effective. Capsorubin accumulates selectively in the nuclei of cancer cells.. The Authors suggest a special complex formation between membrane-bound capsorubin and ascorbic acid, which can be exploited in experimental chemotherapy.

Topics: Animals; Ascorbic Acid; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lung Neoplasms; Lymphoma, T-Cell; Male; Mice; Mice, Inbred CBA; Neoplasms; Pancreatic Neoplasms; Transfection; Xanthophylls; Xenograft Model Antitumor Assays

several studies have shown an inverse relation between vegetable and fruit intake and pancreatic cancer, but no specific beneficial component of such foods has been consistently identified. We considered the role of 15 selected vitamins and carotenoids and 6 minerals on pancreatic cancer risk in an Italian case-control study.. subjects were 326 patients with incident pancreatic cancer and 652 controls, admitted to the same hospitals as cases for acute conditions. Micronutrient computation was based on a validated and reproducible food-frequency questionnaire. We estimated the odds ratios (OR) and confidence intervals (CI) using conditional logistic regression models, adjusted for various confounding factors and for energy intake, according to the residual model.. comparing the highest to the lowest quintile of intake, the OR were 0.60 (95% CI 0.36-0.98) for vitamin E, 0.44 (95% CI 0.27-0.73) for vitamin C, 0.56 (95% CI 0.34-0.93) for folate, and 0.57 (95% CI 0.35-0.92) for potassium. No significant inverse associations were observed for α-carotene (OR = 0.69, 95% CI 0.43-1.12), β-carotene (OR = 0.64, 95% CI 0.39-1.06), and β-cryptoxanthin (OR = 0.66, 95% CI 0.39-1.09). No relation was found for other micronutrients considered.. our findings support a favorable role of vitamins E and C, selected carotenoids, and folate on pancreatic carcinogenesis.

Topics: Adult; Aged; Aged, 80 and over; Ascorbic Acid; Carotenoids; Case-Control Studies; Diet; Female; Humans; Italy; Male; Micronutrients; Middle Aged; Minerals; Pancreatic Neoplasms; Vitamin E

Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial-mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H(2)O(2) derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine-ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma; Cell Line, Tumor; Deoxycytidine; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Synergism; Female; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Deoxycytidine; Drug Synergism; Gemcitabine; Humans; Injections, Intravenous; Mice; Pancreatic Neoplasms; Treatment Outcome

Two popular complementary, alternative, and integrative medicine therapies, high-dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are often coadministered to cancer patients with unclear efficacy and drug-drug interaction. In this study we provide the first survey evidence for clinical use of iv GSH with iv AA. To address questions of efficacy and drug-drug interaction, we tested 10 cancer cell lines with AA, GSH, and their combination. The results showed that pharmacologic AA induced cytotoxicity in all tested cancer cells, with IC(50) less than 4 mM, a concentration easily achievable in humans. GSH reduced cytotoxicity by 10-95% by attenuating AA-induced H(2)O(2) production. Treatment in mouse pancreatic cancer xenografts showed that intraperitoneal AA at 4 g/kg daily reduced tumor volume by 42%. Addition of intraperitoneal GSH inhibited the AA-induced tumor volume reduction. Although all treatments (AA, GSH, and AA+GSH) improved survival rate, AA+GSH inhibited the cytotoxic effect of AA alone and failed to provide further survival benefit. These data confirm the pro-oxidative anti-cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no additional benefit compared with AA alone. There is an antagonism between ascorbate and glutathione in treating cancer, and therefore iv AA and iv GSH should not be coadministered to cancer patients on the same day.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Ascorbic Acid; Carcinoma; Drug Evaluation, Preclinical; Drug Interactions; Female; Glutathione; HeLa Cells; Humans; Infusions, Parenteral; Injections, Intravenous; Mice; Mice, Nude; Pancreatic Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Chalcones are involved in the synthesis of flavonoids and are themselves known to exhibit multiple pharmacological properties. However, compared to other structurally similar phytochemicals like garcinol and curcumin, the therapeutic use of chalcones is limited because of their lower bioavailability and rapid metabolic clearance from biological system. In the present work, we have attempted to overcome these limitations in case of 2'-hydroxychalcones through bioisosteric substitution of fluoro groups in place of phenolic hydroxyls. The fluorinated chalcones were found to be more potent antioxidant and anti-proliferative compounds than their hydroxyl counterparts indicating the influence of metabolically stable C-F bonds towards bioavailability. The difluoro derivatives were found to be most effective against human pancreatic BxPC-3 cancer cells which possess up-regulated COX-2 expression and also showed activity against human breast cancer BT-20 cells with triple negative phenotype, suggesting that these compounds will have broader application in the future.

Topics: Antineoplastic Agents; Antioxidants; Binding Sites; Cell Line, Tumor; Chalcones; Computer Simulation; Cyclooxygenase 2; Halogenation; Humans; Pancreatic Neoplasms; Protein Structure, Tertiary; Superoxide Dismutase; Terpenes

Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%.. Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks.. There was a time- and dose-dependent increase in measured H(2)O(2) production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H(2)O(2). Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival.. These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer.

Topics: Adenocarcinoma; Animals; Ascorbic Acid; Cell Line, Tumor; Cell Survival; Cells, Cultured; Cytotoxins; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide; Mice; Mice, Nude; Oxidative Stress; Pancreatic Neoplasms; Signal Transduction; Xenograft Model Antitumor Assays

To test the hypothesis that polymorphic variants of antioxidant genes modify the risk of pancreatic cancer, we examined seven single-nucleotide polymorphisms (SNPs) of genes coding for superoxide dismutase (SOD) 2, glutathione S-transferase alpha 4 (GSTA4), catalase and glutathione peroxidase in 575 patients with pancreatic adenocarcinoma and 648 healthy controls in a case-control study. Information on risk factors was collected by personal interview and dietary information was collected by a self-administered food frequency questionnaire. Genotypes were determined using the Taqman method. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were estimated by unconditional logistic regression. No significant main effect of genotype was observed. A borderline significant interaction between diabetes and SOD2 Ex2+24T>C CT/TT genotype was observed (P(interaction) = 0.051); the AORs (95% CI) were 0.98 (0.73-1.32) for non-diabetics carrying the CT/TT genotype, 1.73 (0.94-3.18) for diabetics carrying the CC genotype and 3.49 (2.22-5.49) for diabetics carrying the CT/TT genotype compared with non-diabetics carrying the CC genotype. Moreover, the SOD2 -1221G>A AA genotype carriers had a significantly increased risk for pancreatic cancer among those with a low dietary vitamin E intake but decreased risk among those with a high vitamin E intake (P(interaction) = 0.002). There was a non-significant interaction between diabetes and GSTA4 Ex5-64G>A genotypes (P(interaction) = 0.078). No significant interaction between genotype with cigarette smoking or vitamin C intake was observed. These data suggest that genetic variations in antioxidant defenses modify the risk of pancreatic cancer in diabetics or individuals with a low dietary vitamin E intake.

Topics: Adult; Aged; Ascorbic Acid; Diabetes Complications; Female; Genotype; Glutathione Transferase; Humans; Male; Middle Aged; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Risk Factors; Superoxide Dismutase; Vitamin E

Ascorbate (ascorbic acid, vitamin C) is one of the early, unorthodox treatments for cancer. The evidence upon which people base the use of ascorbate in cancer treatment falls into two categories: clinical data on dose concentration relationships, and laboratory data describing potential cell toxicity with high concentrations of ascorbate in vitro. Clinical data show that when ascorbate is given orally, fasting plasma concentrations are tightly controlled by decreased absorption, increased urine excretion, and reduced ascorbate bioavailability. In contrast, when ascorbate is administered intravenously, concentrations in the millimolar level are achieved. Thus, it is clear that intravenous administration of ascorbate can yield very high plasma levels, while oral treatment does not.

Topics: Administration, Oral; Antioxidants; Ascorbic Acid; Autophagy; Humans; Injections, Intravenous; Oxidative Stress; Pancreatic Neoplasms

Ascorbic acid (AA) has been reported to inhibit tumor cell growth through the generation of extracellular hydrogen peroxide (H(2)O(2)). However, the clinical utility of AA has been limited by relatively low potency and in vivo efficacy. This study reports that the metalloporphyrin, Mn(III) tetrakis(N-methylpyridinium-2-yl)porphyrin(5+) (MnTMPyP), has a potent synergistic cytotoxic effect when combined with AA in a variety of cancer cell lines. In the presence of MnTMPyP, the concentration of AA required to inhibit cancer cell growth was markedly reduced. In vitro (cell-free) experiments demonstrated that AA alone enhanced the Fenton reaction that produces cytotoxic hydroxyl radical (HO(*)); however, this reaction was limited by the low rate by which AA generates H(2)O(2) (Fenton reaction substrate) from O(2). MnTMPyP catalyzed H(2)O(2) generation through the AA-facilitated Mn(II <--> III)TMPyP redox cycle and thereby markedly potentiated the Fenton reaction. Accordingly, MnTMPyP and AA resulted in increased cellular levels of H(2)O(2) and HO(*) in cancer cells, which mediate the synergistic cytotoxicity of this combined treatment. This effect was inhibited by cellular enzymes that metabolize H(2)O(2), such as catalase and glutathione peroxidase, suggesting that selective killing of cancer cells deficient in such enzymes can be achieved in vivo.

Topics: Antioxidants; Apoptosis; Ascorbic Acid; Blotting, Western; Catalase; Cell Proliferation; Drug Synergism; Glutathione; Glutathione Reductase; Humans; Hydrogen Peroxide; Hydroxyl Radical; Liver Neoplasms; Male; Manganese; Membrane Potential, Mitochondrial; Metalloporphyrins; Neoplasms, Hormone-Dependent; Oxidation-Reduction; Pancreatic Neoplasms; Prostatic Neoplasms; Reactive Oxygen Species; Superoxides; Tumor Cells, Cultured

To study the effect of recombinant adeno-associated virus (rAAV) vector bearing small inference RNA (siRNA) targeting hypoxia inducible factor 1alpha (HIF-1alpha) combined L: -ascorbate on pancreatic tumors in athymic mice primarily. A cassette encoding siRNA targeting HIF-1alpha mediated by rAAV was constructed, giving rAAV-siHIF. In vitro, rAAV-hrGFP, rAAV-siHIF and L: -ascorbate which were used alone or in combination were delivered to exponentially growing MiaPaCa2 cells. Then, we examined the expression of HIF-1alpha mRNA and protein, the secretion of VEGF in MiaPaCa2 cells under hypoxic condition with Real-time PCR, Western Blot, ELISA, respectively. In vivo, MiaPaCa2 cells were inoculated subcutaneously on the back of nude mice. Nude mice with xenograft tumor were randomly divided into equal groups and were injected with rAAV-hrGFP or rAAV-siHIF or were fed with L: -ascorbate. Then, we measured the size of tumor every 3 days and drew a tumor growth curve. After 30 days, all mice were sacrificed and the tumors were dissected. At last, we examined the expression of HIF-1alpha, VEGF and CD34 by immunohistochemistry and counted micro-vessel density (MVD). In vitro, we found that rAAV-siHIF could inhibit the expression of HIF-1alpha mRNA and protein in MiaPaCa2 human pancreatic cancer cells but L: -ascorbate could only restrain the expression of HIF-1alpha protein. Moreover, rAAV-siHIF and L: -ascorbate could all inhibit the secretion of vascular VEGF. In vivo, we found that rAAV-siHIF could inhibit the growth of nude mice xenograft tumor and the expression of HIF-1alpha and VEGF and MVD while L: -ascorbate can only inhibit the growth of xenograft tumor in the early and middle stage. These results suggest that rAAV-siHIF and L: -ascorbate can inhibit the growth of nude mice xenograft tumor and HIF-1alpha could be a target of pancreatic cancer genetic and pharmacological therapy.

Topics: Animals; Antioxidants; Ascorbic Acid; Blotting, Western; Combined Modality Therapy; Dependovirus; Enzyme-Linked Immunosorbent Assay; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

The aim of the study was to observe the effect of small interference RNA (siRNA) targeting hypoxia-inducible factor 1alpha (HIF-1alpha) combined L-ascorbate on proliferation, migration, and apoptosis of hypoxic MiaPaCa2 human pancreatic cancer cells. A cassette encoding siRNA targeting HIF-1alpha mediated by recombinant adeno-associated virus (rAAV) was constructed, giving rAAV-siHIF. rAAV-siHIF and L-ascorbate, which were used alone or in combination, were delivered to exponentially growing MiaPaCa2 cells under hypoxic conditions. Then, we observed the expression of HIF-1alpha mRNA and protein, the proliferation, apoptosis, and migration of MiaPaCa2 cells by real-time PCR, Western blot, MTT, TUNEL, and Transwell assay, respectively. Under hypoxic conditions, rAAV-siHIF inhibited the expression of HIF-1alpha mRNA in MiaPaCa2 cells but L-ascorbate did not. However, rAAV-siHIF and L-ascorbate both inhibited the expression of HIF-1alpha protein and the proliferation and migration of MiaPaCa2 cells and induced MiaPaCa2 cell apoptosis. The effect in the combined group was more efficient than that seen when rAAV-siHIF or L-ascorbate was used separately. rAAV-siHIF and L-ascorbate both affect biological behavior of hypoxic MiaPaCa2 cells through modulating HIF-1alpha protein expression and rAAV-siHIF and L-ascorbate have synergy under hypoxic conditions.

Topics: Apoptosis; Ascorbic Acid; Cell Hypoxia; Cell Movement; Cell Proliferation; Dependovirus; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Pancreatic Neoplasms; RNA, Small Interfering; Tumor Cells, Cultured

Topics: Ascorbic Acid; Cholesterol; Diet; Dietary Supplements; Humans; Incidence; Japan; Pancreatic Neoplasms; Risk Factors

Current treatment of pancreatic cancer is generally associated with poor prognosis, even if diagnosed early, owing to its aggressive rate of metastasis and non-responsiveness to chemotherapy and radiotherapy. Matrix metalloproteinases (MMPs) have received much attention in recent years for their role in various malignancies, and have been implicated in tumor invasion, metastasis, and angiogenesis.. Reported antitumor properties of ascorbic acid, lysine, proline, and green tea extract prompted us to investigate the effect of a combination of lysine, proline, arginine, ascorbic acid, and green tea extract on pancreatic cancer cell line MIA PaCa-2 for viability, MMP expression, invasion, and morphology.. Viability was evaluated based on cell proliferation by MTT assay and MMP expression in condition media by gelatinase zymography. Invasion through Matrigel was assayed and morphology was observed by hematoxylin and eosin (H+E)staining. Data was analyzed by independent sample "t" test.. The nutrient mixture (NM) did not inhibit cell proliferation at 10 microg/mL and exhibited a dose-dependent antiproliferative effect with maximum inhibition of 38% over the control at 1000 microg/mL. Zymography demonstrated production of only MMP-9, which showed a dose-dependent decreased expression that was abolished at 100 microg/mL of NM. Invasion through Matrigel was inhibited at 10, 50, 100, and 500 microg/mL by 66%, 66%, 87% and 100%, respectively. H&E staining did not indicate changes even at the highest concentration of NM.. Our results suggest that the formulation of green tea extract, lysine, proline, and ascorbic acid, tested as a promising adjunct to standard treatment of pancreatic cancer, by inhibiting MMP expression and invasion without toxic effects important parameters in cancer metastasis.

Topics: Antioxidants; Arginine; Ascorbic Acid; Cell Proliferation; Cell Survival; Humans; Lysine; Matrix Metalloproteinases; Neoplasm Invasiveness; Pancreatic Neoplasms; Proline; Tea; Tumor Cells, Cultured

Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (alpha-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster.. One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1-4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5-8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given alpha-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue.. Retinol and alpha-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins.. Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cricetinae; Disease Models, Animal; Glutathione Peroxidase; Lipid Peroxidation; Liver Neoplasms; Male; Mesocricetus; Neoplasm Metastasis; Nitrosamines; Pancreatic Neoplasms; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vitamin A; Vitamin E

Pancreatic cancer is an aggressive tumor with short median survival and high mortality rate. Alternative therapeutic modalities are currently being evaluated for pancreatic cancer. Here we studied the effects of ascorbyl stearate (Asc-S), a nontoxic, lipophilic derivative of ascorbic acid, on pancreatic cancer. Treatment of human pancreatic carcinoma cells with Asc-S (50-200 microM) resulted in a dose-dependent inhibition of their proliferation. Asc-S slowed down the cell cycle, accumulating, PANC-1 cells in late G2-M phase. Furthermore, Asc-S treatment (150 microM) markedly inhibited growth in soft agar and facilitated apoptosis of PANC-1 cells but not of Capan-2 cells. These effects were accompanied by a significant reduction in insulin-like growth factor 1 receptor (IGF1-R) expression, as compared to untreated controls. Interestingly, Capan-2 cells, the least responsive to Asc-S treatment, did not overexpress the IGF1-R. The results demonstrate the efficacy of Asc-S in inhibing growth of pancreatic cancer cells and warrant additional studies to explore the potential utility of this compound as an alternative and/or adjuvant therapeutic modality for pancreatic cancer.

Topics: Apoptosis; Ascorbic Acid; Capsules; Cell Cycle; Humans; Pancreatic Neoplasms; Receptors, Somatomedin; Tumor Cells, Cultured

Persistent oxidative stress is thought to play an important role in carcinogenesis. Vitamins may influence oxygen radical metabolism and thus inhibit tumor growth. In the present trial the effects of Vitamins (Vit.) A, C and E on neoplastic growth and lipid peroxidation in pancreatic tissue were evaluated on chemically-induced pancreatic adenocarcinoma in the Syrian hamster. The incidence of pancreatic cancer was decreased by Vit. A (64.3%) and Vit. C (71.4%) as compared to the control group (100%, P<0.05). All vitamins increased the activity of superoxidedismutase (SOD) in pancreatic carcinomas. Accumulation of vitamins in tumor cells seems to be responsible for high levels of SOD and consecutive intracellular increase of hydrogen peroxide levels. Since this effect is selectively toxic for tumor cells it might be one of the mechanisms decreasing the incidence of pancreatic cancer in our trial.

Topics: alpha-Tocopherol; Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Cell Division; Cricetinae; Glutathione Peroxidase; Lipid Peroxidation; Mesocricetus; Nitrosamines; Oxidative Stress; Pancreatic Neoplasms; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vitamin A; Vitamins

The effects of vitamins E and E, beta-carotene and selenium on development of N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumours in hamsters were investigated. Dietary supplementation of vitamin C, alone as well as in combination with beta-carotene resulted in consistently lower numbers of advanced ductular lesions. The differences with the controls, however, did not reach the level of statistical significance. Beta-Carotene alone demonstrated no inhibitory effect on the development of (pre)neoplastic lesions in the pancreas. Vitamin E or Se, either alone or in combination, had no effect on the development of advanced ductular lesions in BOP-treated hamsters.

Topics: Adenocarcinoma; Animals; Ascorbic Acid; beta Carotene; Body Weight; Carcinogens; Carcinoma, Ductal, Breast; Carotenoids; Cricetinae; Diet; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreatic Neoplasms; Selenium; Vitamin E

Risk factors for pancreatic cancer were examined in a cohort study of 13,979 residents of a retirement community. After 9 years of follow-up, 65 incident cases of pancreatic cancer were identified. An increased risk of pancreatic cancer was associated with a history of diabetes and cholecystectomy. Higher intake of vegetables, fruits, dietary beta-carotene, and vitamin C were each associated with a reduced risk of pancreatic cancer, although none of these associations was statistically significant. Risk of pancreatic cancer decreased with increasing tea consumption but was unrelated to coffee consumption. No strong or consistent association was seen between either smoking or alcohol consumption and risk of pancreatic cancer, but a consistent and significant increase in risk followed cholecystectomy.

Topics: Aged; Aged, 80 and over; Alcohol Drinking; Ascorbic Acid; beta Carotene; Carotenoids; Cholecystectomy; Coffee; Cohort Studies; Diabetes Mellitus; Diet; Female; Follow-Up Studies; Fruit; Humans; Incidence; Male; Pancreatic Neoplasms; Prospective Studies; Risk Factors; Smoking; Tea; Vegetables

In a hospital-based case-control study of pancreatic cancer conducted in Athens (1991-92), 181 patients with histologically confirmed cancer of the exocrine pancreas were compared with hospital patient controls and hospital visitor controls, individually matched to the cases by hospital, age, gender, and interviewer in a 1:1:1 ratio. All interviews were conducted in person in the respective hospitals. Diet was ascertained through a semiquantitative food-frequency questionnaire. Nutrient intakes for individuals were estimated by multiplying the nutrient content of a selected typical portion-size for each specified food-item by the frequency that the food was used per month, and summing these estimates for all food items. Data were analyzed using conditional logistic regression, controlling for tobacco smoking and total energy intake as well as for mutual confounding influences among nutrients. Adjusted odds ratios (rate ratios) for pancreatic cancer, associated with particular nutritional variables, were expressed per increments approximately equal to the standard deviations of (the residual of) the respective nutrients, on a daily basis. The adjusted odds ratios (OR) and 95 percent confidence intervals (CI) compared with other patient and visitor controls respectively, were: for polyunsaturated fat, OR = 1.32 (CI = 1.07-1.63) and 1.21 (CI = 0.98-1.49); and for crude fibre, OR = 0.80 (CI = 0.64-1.00) and 0.65 (CI = 0.50-0.86). No substantial, statistically significant or consistent, independent associations were noted for total energy, total protein, total fat, saturated fat, monounsaturated fat, dietary cholesterol, total carbohydrates, sucrose, vitamin C, vitamin A, riboflavin, or calcium.

Topics: Ascorbic Acid; Case-Control Studies; Diet; Dietary Fats; Dietary Fiber; Energy Intake; Fatty Acids, Unsaturated; Feeding Behavior; Greece; Humans; Nutritional Physiological Phenomena; Pancreatic Neoplasms; Risk Factors; Vitamin A

A study was made on the effects of long-term dietary administration of beta-carotene, vitamin C, vitamin E and selenium, either alone or in combination, on azaserine-induced pancreatic carcinogenesis in rats. Male Wistar rats were given two i.p. injections of 30 mg azaserine per kg body weight at 19 and 26 days of age. The rats were allocated to eight groups of 40 animals each and were fed an AIN-76 diet rich in saturated fat (20% lard), either as such or after supplementation with beta-carotene, vitamin C, beta-carotene + vitamin C, vitamin E, selenium, vitamin E + selenium, or the combination of all micronutrients investigated. Fifteen months after the last treatment with azaserine the survivors were killed. The pancreata were examined for the number and size of advanced putative preneoplastic lesions and the number of neoplasms as well. Rats maintained on a diet high in either beta-carotene, vitamin C or selenium developed significantly less atypical acinar cells nodules, adenomas and carcinomas as compared to controls. The number of tumour-bearing animals was significantly lower in the groups fed the diet high in beta-carotene or selenium. In animals of the group given a diet high in all micronutrients investigated, both the number and incidence of pancreatic tumours was lower than in all other groups. It was concluded that selenium, beta-carotene and vitamin C, alone as well as in combination, have an inhibitory effect on pancreatic carcinogenesis induced in rats by azaserine.

Topics: Animals; Ascorbic Acid; Azaserine; beta Carotene; Body Weight; Carotenoids; Diet; Drug Combinations; Liver; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Regression Analysis; Selenium; Vitamin E

The effects of vitamins A, C and E on the development of putative preneoplastic foci in exocrine pancreas were investigated in azaserine-treated rats and N-nitrosobis(2-oxoproypy)amine-treated hamsters. The animals were fed a semipurified diet high in saturated fat (20% lard) either or not supplemented with vitamin A, vitamin C or vitamin E. A separate group maintained on a diet low in saturated fat (5% lard) was incorporated as extra controls. The animals were given their diets 12 days after the last treatment with carcinogen. At 4 months postinitiation, the pancreata were quantitatively examined for both the number and size of early, putative preneoplastic lesions and the presence of neoplastic lesions. Rats as well as hamsters maintained on 5% lard exhibited a significantly lower number of putative preneoplastic pancreatic lesions than animals fed a diet containing 20% lard. Growth of acidophilic but not of basophilic foci was inhibited in rats of the high vitamin A and C group, whereas vitamin E exerted an inhibitory effect on growth of basophilic but not of acidophilic foci. In hamsters maintained on a diet high in vitamins A or C, the number of early ductular lesions was significantly decreased, whereas the number of (micro)carcinomas was increased. Vitamin E did not have any modulating effect on development of ductal lesions in hamster pancreas.

Topics: Animals; Ascorbic Acid; Cricetinae; Dietary Fats; Energy Metabolism; Male; Mesocricetus; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Vitamin A; Vitamin E

The biological mode of action of tumor promoters, exemplified by the phorbol esters, is a subject of intensive study in a number of laboratories. A few investigators have recently begun to examine the role of dietary nutrients in tumor promotion, but the available data are sparse and interpretation difficult. A few examples are provided to indicate that some nutrients may be important in the promotion of cancer. However, the fine dividing line between effects on initiation or on promotion, so clearly shown in the mouse two-stage skin cancer model, is not so clear as yet in models used for studies in nutritional carcinogenesis. The animal models for these studies have been primarily rats, mice and hamsters. These have shown that nutrients which appear to have promotion activity are zinc deficiency and 13-cis-retinoic acid for the esophagus; vitamin A deficiency and lipotrope deficiency for the forestomach, unsaturated fat and vitamin A deficiency for liver and colon, lipotrope deficiency for the liver; selenium for the liver. It is probably more correct at this early stage of investigation to consider the effects of nutrients acting either during the time of exposure to the carcinogen, or, after such exposure and when no detectable carcinogen is found in the animals tissues, rather than as promoters in the strict sense.

Topics: Animals; Ascorbic Acid; Carcinogens; Cocarcinogenesis; Colonic Neoplasms; Cricetinae; Diet; Disease Models, Animal; Esophageal Neoplasms; Gastrointestinal Neoplasms; Liver Neoplasms; Mice; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Zinc

Topics: Adult; Ascorbic Acid; Female; Humans; Intestinal Absorption; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pyridoxine; Riboflavin; Thiamine; Vitamin A; Vitamins