Treating pancreatic cancer: more antioxidants more problems?
Ontology highlight
ABSTRACT:
SUBMITTER: Alexander MS
PROVIDER: S-EPMC6317716 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Treating pancreatic cancer: more antioxidants more problems?
Alexander Matthew S MS Cullen Joseph J JJ
Expert review of gastroenterology & hepatology 20180705 9
Similar Datasets
Project description:Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases. Therefore, it is not surprising that considerably less attention has been given to studying physiological functions of pancreatic stellate cells. Here, we review recent advances not only in the field of pancreatic stellate cell pathophysiology but also emphasise their roles in physiological processes.
| S-EPMC5554282 | biostudies-other
Project description: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.
| S-EPMC2847085 | biostudies-literature
Project description:Patients with pancreatic cancer have not benefited from recent improvements in overall survival brought about by precision medicine in other malignancies. This failure is not due to a dearth of precision-medicine research in pancreatic ductal adenocarcinoma (PDAC), the main type of pancreatic cancer. In fact, the stalled progress in precision therapies for this type of cancer is due to the absence of agents that are able to target the common genetic alterations in PDAC. Several studies have attempted to phenotypically stratify PDAC at the transcriptional level. However, the value of such classifications will only be revealed through prospective studies and, crucially, only after development of new treatment options for this disease. Therefore, it is essential to learn from breakthrough discoveries in other cancer types that could benefit subpopulations of patients with PDAC and convert them from ordinary to exceptional responders. Identifying these exceptional patients will help to bring PDAC in line with other cancer types in terms of availability of precision therapies. Thus, the true challenge to precision medicine for PDAC might be the poor consensus on which genetic and phenotypic alterations across the spectrum of this disease are actionable; not the absence of actionable variables themselves. To reach consensus, knowledge and tools must be developed and disseminated for individuals who provide pancreatic cancer care, to enable the real-time identification of exceptional patients, more precise subgroup classifications, and effective disease management strategies; all informed by immediate feedback from clinical outcome data.
| S-EPMC9516437 | biostudies-literature
Project description:The objective of this study was to design GE11 peptide (YHWYGYTPQNVI) linked micelles of poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-gemcitabine-graft-dodecanol (PEG-b-PCC-g-GEM-g-DC) for enhanced stability and target specificity of gemcitabine (GEM) to EGFR-positive pancreatic cancer cells. GE11-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles showed EGFR-dependent enhanced cellular uptake, and cytotoxicity as compared to scrambled peptide HW12-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles and unmodified mPEG-b-PCC-g-GEM-g-DC micelles. Importantly, GE11-linked mixed micelles preferentially accumulated in orthotopic pancreatic tumor and tumor vasculature at 24 h post systemic administration. GE11-linked mixed micelles inhibited orthotopic pancreatic tumor growth compared to HW12-linked mixed micelles, unmodified mPEG-b-PCC-g-GEM-g-DC micelles, and free GEM formulations. Tumor growth inhibition was mediated by apoptosis of tumor cells and endothelial cells as determined by immunohistochemical staining. In summary, GE11-linked mixed micelles is a promising approach to treat EGFR overexpressing cancers.
| S-EPMC4829353 | biostudies-literature
Project description:To investigate whether polymorphisms in genes related to oxidative stress act alone or in combination with antioxidants to modulate pancreatic cancer risk. Cases (n=189), ages ? 20 years, were ascertained in 1994-1998 from all hospitals in the Twin Cities and the Mayo Clinic. Controls (n=486) were randomly selected from the general population and frequency matched to cases by age and sex. After adjustment for confounders, individuals who were homozygous or heterozygous for the variant allele of SOD2 polymorphism (Ala16Val, rs4880) experienced a 43% lower risk than those who were homozygous for the wild-type allele [OR (95% CI): 0.57 (0.37, 0.89)]. Conversely, an increased risk was observed for the variant allele of hOGG1 polymorphism (Ser326Cys, rs1052133) compared with the wild-type allele [OR (95% CI) for Ser/Cys or Cys/Cys vs. Ser/Ser: 1.57 (1.04, 2.39)]. The protective effect of the variant allele of SOD2 was more pronounced among subjects with a low dietary intake (<median) of lutein/ zeaxanthin, lycopene, ?-carotene, and ?-tocopherol [OR (95% CI): 0.46 (0.27, 0.81), 0.42 (0.23, 0.75), 0.47 (0.26, 0.85), and 0.48 (0.27, 0.87), respectively]. Individual variations in the capacity to defend against oxidative stress and to repair oxidative DNA damage influence pancreatic cancer risk, and some of these genetic effects are modified by dietary antioxidants.
| S-EPMC3166151 | biostudies-literature
Project description: Not available
| S-EPMC11399858 | biostudies-literature
Project description:Successful treatment of pancreatic ductal adenocarcinoma (PDAC) remains a challenge due to the desmoplastic microenvironment that promotes both tumor growth and metastasis and forms a barrier to chemotherapy. Hedgehog (Hh) signaling is implicated in initiation and progression of PDAC and also contributes to desmoplasia. While Hh levels are increased in pancreatic cancer cells, levels of tumor suppressor miR-let7b, which targets several genes involved in PDAC pathogenesis, is downregulated. Therefore, our overall objective was to inhibit Hh pathway and restore miR-let7b simultaneously for synergistically treating PDAC. miR-let7b and Hh inhibitor GDC-0449 could inhibit the proliferation of human pancreatic cancer cells (Capan-1, HPAF-II, T3M4, and MIA PaCa-2), and there was synergistic effect when miR-let7b and GDC-0449 were coformulated into micelles using methoxy poly(ethylene glycol)-block-poly(2-methyl- 2-carboxyl-propylenecarbonate-graft-dodecanol-graft-tetraethylene-pentamine) (mPEG-b-PCC-g-DC-g-TEPA). This copolymer self-assembled into micelles of <100 nm and encapsulated hydrophobic GDC-0449 into its core with 5% w/w drug loading and allowed complex formation between miR-let7b and its cationic pendant chains. Complete polyplex formation with miRNA was observed at the N/P ratio of 16/1. Almost 80% of GDC-0449 was released from the polyplex in a sustained manner in 2 days. miRNA in the micelle formulation was stable for up to 24 h in the presence of serum and high uptake efficiency was achieved with low cytotoxicity. This combination therapy effectively inhibited tumor growth when injected to athymic nude mice bearing ectopic tumor generated using MIA PaCa-2 cells compared to micelles carrying GDC-0449 or miR-let7b alone. Immunohistochemical analysis revealed decreased tumor cell proliferation with increased apoptosis in the animals treated with miR-let7b and GDC-0449 combination.
| S-EPMC4829351 | biostudies-literature
Project description:Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. Here, we show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by inactivating the ROS-p53 axis. Because p53 inactivation occurs late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.
2014-01-31 | GSE52594 | GEO
Project description:Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. Here, we show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by inactivating the ROS-p53 axis. Because p53 inactivation occurs late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. There were 3 experimental groups (untreated, NAC-treated and Vitamin E-treated. Each group consisted of 5 animals, and from each animal we harvested 2 tumor samples. Hence, in total 3x10=30 samples were profiled.
2014-01-31 | E-GEOD-52594 | biostudies-arrayexpress
Project description:A highly efficient antioxidant is developed by encapsulating superoxide dismutase (SOD) within the aqueous interior of porous polymersomes. The porous polymersomes provide a permeable membrane that allows free superoxide radicals to pass into the aqueous interior and interact with the encapsulated antioxidant enzyme SOD. In vivo studies in the rat demonstrate that administration of SOD-encapsulated porous polymersomes can prevent neuropathic pain after nerve root compression more effectively than treatment with free antioxidant enzyme alone.
| S-EPMC5591629 | biostudies-literature