4-hydroxy-2-nonenal and Adenocarcinoma

Barrett's esophagus (BE), a chronic inflammatory condition, is the leading risk factor for esophageal adenocarcinoma (EAC). In inflammation to cancer pathways, oxidative stress profiles have been linked to cancer progression. However, the relevance of oxidative stress profiles along the BE-disease sequence remains to be elucidated. In this study, markers of oxidative stress; DNA adducts (8-oxo-dG) and lipoperoxidation (4-HNE), and markers of proliferation (Ki67) were measured in patient biopsies representing the BE-disease sequence. Differences in expression of these markers in Barrett's patients with cancer-progression and non-progression were examined. Proliferation was reduced in Barrett's specialized intestinal metaplasia (SIM) compared with EAC (

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Aldehydes; Apoptosis; Barrett Esophagus; Cell Proliferation; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Oxidative Stress; Transcriptome

The expression levels of human antioxidant genes (HAGs) and oxidative markers were investigated in light of lung adenocarcinoma aggressiveness and patient outcome.. We assayed in vitro the tumoral invasiveness and multidrug resistance in human lung adenocarcinoma (AdC) cell lines (EKVX and A549). Data were associated with several redox parameters and differential expression levels of HAG network. The clinicopathological significance of these findings was investigated using microarray analysis of tumor tissue and by immunohistochemistry in archival collection of biopsies.. An overall increased activity (expression) of selected HAG components in the most aggressive cell line (EKVX cells) was observed by bootstrap and gene set enrichment analysis (GSEA). In vitro validation of oxidative markers revealed that EKVX cells had high levels of oxidative stress markers. In AdC cohorts, GSEA of microarray datasets showed significantly high levels of HAG components in lung AdC samples in comparison with normal tissue, in advanced stage compared with early stage and in patients with poor outcome. Cox multivariate regression analysis in a cohort of early pathologic (p)-stage of AdC cases showed that patients with moderate levels of 4-hydroxynonenal, a specific and stable end product of lipid peroxidation, had a significantly less survival rate (hazard ratio of 8.87) (P < 0.05).. High levels of oxidative markers are related to tumor aggressiveness and can predict poor outcome of early-stage lung adenocarcinoma patients.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Aldehydes; Antioxidants; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lipid Peroxidation; Lung Neoplasms; Male; Microarray Analysis; Middle Aged; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Odds Ratio; Oxidation-Reduction; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Retrospective Studies

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Adenocarcinoma; Aldehydes; Animals; Antibiotics, Antineoplastic; Apoptosis; Caspase 3; Catheter Ablation; Chemotherapy, Adjuvant; Combined Modality Therapy; Deoxyguanosine; DNA Damage; Doxorubicin; Histones; HSP70 Heat-Shock Proteins; Humans; Liver Neoplasms; Mammary Neoplasms, Experimental; Oxidative Stress; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Tyrosine

Clinical use of retinoic acids (RA) is hindered by toxicity possibly related to oxidative stress. Recently, RA at relatively low concentrations was shown to inhibit NRF2 and the expression of its target antioxidative genes. This raises the possibility that RA toxicity may result from cellular inability to cope with resultant oxidative stress. Using in vitro cell and in vivo mouse models, we report that RA, specifically all-trans-RA (atRA) at concentrations implicated in toxicity, can activate NRF2 and induce NRF2 target genes, particularly the subunits of the rate-limiting enzyme of glutathione biosynthesis, glutamate cysteine ligase (GCLM/GCLC). RNA interference-mediated silencing of NRF2, but not of retinoid X receptor-alpha and -beta, reduced basal and atRA-induced GCLM/GCLC gene expression. Moreover, RA increased nuclear accumulation of NRF2, antioxidant response element (ARE) reporter activity, and NRF2 occupancy at AREs. 4-Hydroxynonenal, a lipid peroxidation product, was increased by RA. Inhibition of MEK1/ERK mitogen-activated protein kinases significantly suppressed atRA-induced NRF2 activation and ARE-regulated gene expression, reducing cell resistance against toxic concentrations of RA. NRF2-silenced cells were vulnerable to atRA-induced mitochondrial toxicity and apoptosis. In conclusion, toxic RA activates NRF2, thereby triggering an adaptive response against the resultant oxidative stress. NRF2 enhancement as a therapeutic target of retinoid toxicity awaits further investigation.

Topics: Adenocarcinoma; Aldehydes; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Breast Neoplasms; Carcinoma, Hepatocellular; Cells, Cultured; Gene Expression Regulation; Glutamate-Cysteine Ligase; Humans; Kidney; Lipid Peroxidation; Liver Neoplasms; Male; MAP Kinase Kinase 1; Mice; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-E2-Related Factor 2; Response Elements; Retinoid X Receptor alpha; Retinoid X Receptor beta; RNA, Small Interfering; Tretinoin

In A549 cell culture, significant variability was found in sensitivity to actinomycin D. Using limiting dilution, actinomycin D-susceptible (G4S) and -resistant (D3R) subclones were isolated. G4S cells were also susceptible to protein synthesis inhibitors, a redox cycling quinone, and an electrophile with concomitant activation of caspases 3 and 9. D3R cells were resistant to these agents without caspase activation. Antioxidant profiles revealed that D3R cells had significantly higher glutathione and glutathione reductase activity but markedly lower catalase, glutathione peroxidase, and aldehyde reductase activities than G4S cells. Thus A549 cells contain at least two distinct subpopulations with respect to predisposition to cell death and antioxidant profile. Because sensitivities to agents and the antioxidant profile were inconsistent, mechanisms independent of antioxidants, including the apparent inability to activate caspases in D3R cells, may play an important role. Regardless, the results suggest that antioxidant profiles of asymmetrical cell populations cannot predict sensitivity to oxidants and warn that the use of single subclones is advisable for mechanistic studies using A549 or other unstable cell lines.

Topics: Adenocarcinoma; Aldehydes; Anisomycin; Antioxidants; Apoptosis; Caspases; Cytotoxins; Dactinomycin; Genetic Heterogeneity; Glutathione; Growth Inhibitors; Humans; Hydrogen Peroxide; Lung Neoplasms; Male; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Protein Synthesis Inhibitors; Superoxide Dismutase; Tumor Cells, Cultured

This study was done to discover the underlying mechanism of the inhibitory effect of sericin against colon tumorigenesis. Mice were fed a diet with 30 g/kg sericin for 115 d, and given a weekly injection of 1,2-dimethylhydrazine (10 mg/kg body weight) for the initial 10 wk. Dietary supplemental sericin caused a 62% reduction in the incidence of colonic adenoma (P<0.05), but did not affect the incidence of colonic adenocarcinoma. Sericin intake significantly reduced the number of colon adenomas. Consumption of sericin significantly reduced the BrdU labeling index of colonic proliferating cells and the expression of colonic c-myc and c-fos. The levels of colonic 8-hydroxydeoxyguanosine, 4-hydroxynonenal, and inducible nitric oxide synthase protein were significantly suppressed by sericin. The results suggest that dietary sericin suppresses the development of colon tumors by reducing oxidative stress, cell proliferation, and nitric oxide production.

Topics: 1,2-Dimethylhydrazine; 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adenoma; Aldehydes; Animals; Apoptosis; Carcinogens; Cell Division; Colonic Neoplasms; Deoxyguanosine; Immunohistochemistry; Intestinal Mucosa; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Peptides, Cyclic; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Sericins

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3-nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adenoma; Adult; Aged; Aldehydes; Case-Control Studies; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Deoxyguanosine; Epithelial Cells; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nitrates; Oxidants; Oxidative Stress; Reactive Oxygen Species; Time Factors