Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the possible role of NF-kappaB in mouse skin carcinogenesis we studied the expression of p50 (NF-kappaB1), p52 (NF-kappaB2), p65 (RelA) and IkappaB-alpha inhibitor as well as kappaB-binding activity in adult SENCAR mouse skin, skin papillomas, and squamous cell carcinomas (SCC) generated by a two-stage carcinogenesis protocol. We found that in normal epidermis all of the above proteins were mostly expressed in the cytoplasm of basal cells. Western blot analysis revealed a dramatic increase of p50 and p52 expression in mouse skin tumors starting from the middle stage of promotion. We also found that the level of IkappaB-alpha protein in many late papillomas and SCC was lower than in normal epidermis. Results of EMSA showed an increase in kappaB-binding activity in mouse skin tumors and suggested that p50 is the major component of constitutive kappaB-binding complexes in normal epidermis and in tumors. It has been shown that nuclear IkappaB protein Bcl-3 is able to increase p50/p50 homodimer binding to the different kappaB sites in mouse thymocytes. Our finding on Bcl-3 overexpression in late papillomas and SCC could explain the selective increase of p50-related kappaB-binding in mouse skin tumors. Thus, our results strongly suggest the important role of p50 in skin carcinogenesis.
 ...
PMID:Increased expression of p50-NF-kappaB and constitutive activation of NF-kappaB transcription factors during mouse skin carcinogenesis. 1060 1

Free radicals are highly reactive species that have been implicated in the pathogenesis of many diseases. Reactive oxygen species can initiate lipid peroxidation and DNA damage leading to mutagenesis, carcinogenesis and cell death, if the antioxidant system is impaired. This study was undertaken to examine the prevalence of oxidative stress and the role of antioxidant defence in untreated leukemia patients. The generation of superoxide anion and hydrogen peroxide by leukocytes, plasma malondialdehyde levels, red cell copper zinc superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GSH-PX) activities were determined in 30 patients with different types of leukemias prior to therapy. The superoxide anion generation by polymorphonuclear leukocytes was found to be significantly increased in leukemia patients especially those with acute lymphocytic and nonlymphocytic leukemias, while the hydrogen peroxide levels were comparable to the control values. Plasma lipid peroxidation products in untreated leukemia patients were in the normal range. Red cell Cu-Zn SOD and GSH-PX activities were significantly increased and showed no correlation with the hemoglobin content. Although superoxide generation was high, lipid peroxide levels were normal in these patients. This might be due to the increased activities of the antioxidant enzymes (SOD, GSH-PX) which counteract lipid peroxidation. Increased free radical generation, especially superoxide anion in leukemia patients and increased antioxidant defence enzymes, which is an adaptive protective response, are indicative of mild oxidative stress. There were no significant differences for the parameters cited above between different types of leukemias, suggesting that the changes are not specific to the type of leukemia.
 ...
PMID:Free radicals antioxidant enzymes and lipid peroxidation in different types of leukemias. 1069 22

S100A2 is a calmodulin-like protein of unknown function, whose transcription is positively regulated in response to ErbB and p53 signaling. Expression of S100A2 is markedly increased in the context of ErbB-driven reactive epidermal hyperplasia, and decreased in the context of hypofunctional p53 mutations in carcinoma cell lines and tumors. This bimodal pattern of regulation suggests an important function for S100A2 in keratinocyte differentiation and carcinogenesis. Taking the biochemical approach to the determination of S100A2 function, we have characterized its physical state and subcellular localization in normal human keratinocytes. S100A2 in hypotonic lysates remained soluble after centrifugation at 100 000 x g, indicating that it is not associated with cell membranes. Permeabilization experiments confirmed the lack of membrane association and revealed a digitonin-insoluble nuclear fraction of S100A2, which was confirmed by immunofluorescence microscopy. Pulldown assays of epitope-tagged S100A2 and yeast two-hybrid screening revealed that S100A2 displays a strong propensity to homodimerize. Naturally expressed S100A2 dimers in normal human keratinocytes readily underwent intermolecular disulfide cross-linking unless a strong denaturant was present during cell lysis. Treatment of intact normal human keratinocytes with hydrogen peroxide strongly promoted S100A2 cross-linking. These results demonstrate that native S100A2 is a homodimer that does not depend on disulfide cross-linking for stability, but undergoes intermolecular cross-linking at cysteine residues in response to oxidative stress. Based on these findings, we propose that S100A2 may protect normal keratinocytes against carcinogens by participating in the cellular proof-reading response to oxidative stress.
 ...
PMID:Biochemical characterization of S100A2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking. 1095 Dec 87

Potassium bromate (KBrO3), a food additive, induces renal-cell tumors in rats. KBrO3 induced 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) formation in human leukemia cell line HL-60 as well as in its H2O2-resistant clone, HP100, suggesting no involvement of H2O2. Depletion of GSH by buthionine sulfoximine (BSO) had a little inhibitory effect on KBrO3-induced 8-oxodG formation. However, the amount of 8-oxodG was still significantly higher than that in control, suggesting that intracellular Cys can affect KBrO3 to oxidize DNA, when GSH decreased. KBrO3 caused 8-oxodG in isolated DNA in the presence of GSH (tripeptide; gamma-GluCysGly), gamma-GluCys, CysGly, or Cys. Methional completely inhibited 8-oxodG formation induced by KBrO3 plus GSH, but typical hydroxyl radical scavengers, SOD and catalase, had little or no inhibitory effects. When bromine solution (BrO(-)) was used instead of BrO3(-), similar scavenger effects were observed. Experiments with 32P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene suggested that KBrO3 induced 8-oxodG formation at 5'-site guanine of GG and GGG sequences of double-stranded DNA in the presence of GSH and that treatment of formamidopyrimidine-DNA glycosylase led to chain cleavages at the guanine residues. ESR spin-trapping studies showed that 1:2:2:1 quartet DMPO (5,5-dimethyl-1-pyrroline N-oxide) spectrum similar to DMPO/hydroxy radical (*OH) adduct, but the signals were not inhibited by ethanol. Therefore, the signal seemed not to be due to *OH but byproduct due to oxidation of DMPO by the reactive species. The signals were suppressed by the addition of dGMP, but not by other mononucleotides, suggesting the specific reactivity with guanine. On the basis of our results and previous literature, it is speculated that reduction of KBrO3 by SH compounds in renal proximal tubular cells yields bromine oxides and bromine radicals, which are the reactive species that cause guanine oxidation, leading to renal carcinogenesis of KBrO3.
 ...
PMID:Requirement of glutathione and cysteine in guanine-specific oxidation of DNA by carcinogenic potassium bromate. 1140 38

A balance between oxidant carcinogens and endogenous antioxidant defence is of particular relevance to the carcinogenesis. Ceruloplasmin (Cp) carries up to 90% of Cu in plasma and performs ferroxidase, antioxidant and amine oxidase activity. Cu and Zn, as trace elements, have been recognized to play an important role as cofactors of SOD. The study presents the relationship of the Cp oxidase activity and concentrations of Cu and Zn in serum of 62 patients with breast (BCA), lung (LCA), gastrointestinal (GICA) and gynecological (GYNCA) cancer. The Cp oxidase activity was determined in serum with o-dianisidine as a substrate. Cu and Zn concentrations in serum were measured by using atomic absorption spectrometry. The results of the study have shown significant increase in the mean serum Cp oxidase activity and total Cu concentrations in all patient groups compared with the control one. The total mean serum Zn concentration was found to be decreased only in LCA group as compared with the control. The effect of the cancer progress on the Cp oxidase activity and concentrations of Cu and Zn was observed within the group of all cancer patients (ALLCA) and within the GICA group. The only significant difference in Cu concentrations among various stages of the disease was observed in GICA between local and distant one. Significant positive correlation coefficients were caLculated for the Cp activity and Cu concentrations in the control group and all patients groups, also according to the cancer progress. Future research is needed to evaLuate the consequences of the elevation of the serum Cp oxidase activity and concentration of Cp, Cu and Zn for the host antioxidant-oxidant balance.
 ...
PMID:Oxidase activity of ceruloplasmin and concentrations of copper and zinc in serum of cancer patients. 1178 88

Adduct formation has been considered to be a major causal factor of DNA damage by carcinogenic heterocyclic amines. By means of experiments with an electrochemical detector coupled to a high-performance liquid chromatograph, we revealed that N-hydroxy metabolite of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) induced the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in the presence of Cu(II). Addition of an endogenous reductant NADH enhanced the 8-OH-dG formation. Experiments with (32)P-labeled DNA fragments showed that this metabolite [PhIP(NHOH)] caused 8-hydroxylation of guanines in the presence of Cu(II) and NADH, and subsequent treatment with formamidopyrimidine-DNA glycosylase led to chain cleavages at the 5'-site guanine of GG and GGG sequences. Interestingly, antioxidant enzyme SOD enhanced the intensity of DNA damage, and thymine residues were appended to its guanine-predominant cleavage sites. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). A UV-visible spectroscopic study indicated that Cu(II) and SOD catalyze the autoxidation of PhIP(NHOH). These results suggest that Cu(II)-dependent autooxidation of PhIP(NHOH) coupled with NADH-mediated reduction of its oxidized product form redox cycle, resulting in oxidative DNA damage by low concentrations of PhIP(NHOH). We conclude that in addition to DNA adduct formation, oxidative DNA damage may be involved in the carcinogenic process of PhIP.
Carcinogenesis 2002 May
PMID:Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH. 1201 60

We examined the mechanism of DNA damage induced by carcinogenic Ni(II) in the presence of SH compounds. In the presence of model endogenous SH compounds, dithiothreitol (DTT), 1,4-dithio-L-threitol, and dithioerythritol, Ni(II) induced damage to (32)P-5'-end-labeled DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. The intensity of Ni(II)-mediated DNA damage induced by DTT was stronger than that by other model endogenous SH compounds, 1,4-dithio-L-threitol and dithioerythritol. DNA damage induced by Ni(II) plus DTT was observed only when the DNA was treated with piperidine, suggesting that Ni(II) plus DTT caused only base damage. Formamidopyrimidine-DNA glycosylase, which is known to recognize 8-oxodG as well as Fapy residues, treatment induced cleavage sites, mainly guanine residues, particularly at the 5'-GG-3', 5'-GGG-3', and 5'-GGGG-3' sequences, in DNA incubated with Ni(II) in the presence of DTT. SOD and catalase inhibited the DNA damage, suggesting that DNA damage involved superoxide anion and hydrogen peroxide. Sodium azide, a potent and relatively specific scavenger of (1)O(2), inhibited DNA damage by Ni(II) in the presence of DTT, whereas the sequence specificity of DNA damage was different from that obtained by (1)O(2) generating agent. The formation of 8-oxodG in calf thymus DNA by Ni(II) was observed with the physiological thiols, dihydrolipoic acid and mercaptopyruvate, as well as with DTT. These results suggest that Ni(II) and DTT form a reactive species, which may be responsible for causing guanine-specific DNA damage. Endogenous SH compounds, which have similar chemical structures to DTT, would participate in nickel carcinogenesis through causing oxidative DNA damage.
 ...
PMID:Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds: comparison with singlet oxygen-induced DNA damage. 1218 85

Selective inhibition of eicosanoid synthesis is thought to have effects on carcinogenesis in lung and colon cancer. However, it is still unknown whether pancreatic cancer might also be influenced. Therefore we evaluated the impact of selective cyclooxygenase-2 inhibitor Celebrex and selective 5-lipoxygenase inhibitor Zyflo on liver metastasis in a solid model of pancreatic adenocarcinoma in Syrian hamster. In week 33, the animals were sacrificed and incidence of pancreatic carcinomas and number and size of liver metastases were determined. Activities of antioxidative enzymes (GSHPX/SOD) and concentrations of products of lipidperoxidation were measured in liver metastases and non-metastatic hepatic tissue. The incidence (54.5 vs. 100%), number (3.17 +/- 0.98 vs. 6.75 +/- 0.71) and size (2.67 +/- 1.97 vs. 11.75 +/- 1.98 mm2) of liver metastases were decreased by combined therapy of Zyflo and Celebrex (P < 0.05). Furthermore, activities of GSHPX ([73.77 +/- 5.67]*10(5) vs. [15.49 +/- 4.02]*10(5) U/mg prot.; P < 0.05) and SOD (474.92 +/- 108.8 vs. 127.89 +/- 38.75 U/mg prot.; P < 0.05) were increased, while lipidperoxidation (0.31 +/- 0.08 nmol/mg prot. vs. 1.54 +/- 0.55 nmol/mg prot.; P < 0.05) was decreased by combination therapy, in non-metastatic hepatic tissue. Moreover, combined therapy increased lipidperoxidation in liver metastases (0.47 +/- 0.09 vs. 1.95 +/- 0.12 nmol/mg prot.; P < 0.05). Thus, a combination of Celebrex and Zyflo might be a new concept to decrease tumour growth in liver metastases in advanced pancreatic cancer.
 ...
PMID:Effects of Celebrex and Zyflo on liver metastasis and lipidperoxidation in pancreatic cancer in Syrian hamsters. 1255 73

AIDS-related Kaposi's sarcoma (AIDS-KS), which is the most prevalent AIDS related cancer, arises in a unique environment characterized by profound immunosuppression in conjunction with sustained immunostimulation. Persistent inflammation and the accompanying increased production of reactive species can promote carcinogenesis by numerous routes including sustained cell proliferation, initiation of nuclear and mitochondrial DNA mutations and induction of a proangiogenic environment. Furthermore, during conditions of continuous inflammation, protein nitration can result in irreversible inactivation of enzymes including the cytoprotective and reactive species degrading enzyme, mitochondrial superoxide dismutase (MnSOD). Because MnSOD serves as a putative tumor suppressor gene in addition to its reactive species inactivating capacities, the loss of MnSOD's cytoprotective functions could markedly facilitate malignant transformation. The purpose of this study was to investigate biochemical and molecular pathways by which reactive species facilitate AIDS-KS pathogenesis. Immunohistochemical studies of AIDS-KS tumors showed intense AIDS-KS lesional cell staining for MnSOD, inducible nitric oxide synthase (NOS 2) and the presence of a cellular 'fingerprint' of nitrative stress, 3-nitrotyrosine. Collectively, these results that imply reactive species stress occurs in situ. Similarly, cultured AIDS-KS cells derived from the AIDS-KS tumors contained both MnSOD protein and the 'high output' isoform, NOS 2. Co-localization studies established that the mitochondria are a primary site for 3-nitrotyrosine localization and immunoprecipitation/immunoblotting experiments confirmed that MnSOD tyrosine nitration occurs in AIDS-KS cells. Functional SOD assays showed that AIDS-KS cells possess significantly lower MnSOD activity relative to matched control cells; findings which correspond with ongoing MnSOD tyrosine nitration and subsequent inactivation within AIDS-KS cells. These results, which show in situ evidence of reactive species stress within AIDS-KS tumors and functional deficits attributable to nitrative stress in tumor-derived AIDS-KS lesional cells, imply that reactive species are intimately associated with AIDS-KS pathogenesis and provide insights for development of novel strategies for AIDS-KS clinical treatments.
Carcinogenesis 2004 Apr
PMID:Implications for oxidative and nitrative stress in the pathogenesis of AIDS-related Kaposi's sarcoma. 1465 37

Vanadium (V) has recently been found to possess potent anti-neoplastic activity in rat colon carcinogenesis. In the present study attempts have been made to investigate the expression of the number and area of aberrant crypt foci positive for placental glutathione S-transferase (GST-P) during 1,2-dimethyl hydrazine (DMH)-induced rat colon carcinogenesis. Male Sprague Dawley rats were randomly divided into four groups. Rats in group A were designed as normal controls. Group B animals received DMH once a week (20 mg/kg body wt.) intraperitoneally for 16 weeks. Group C rats received the same treatment of DMH as in group B, along with 0.5-ppm vanadium as ammonium monovanadate ad libitum in drinking water throughout the experiment. Vanadium alone was given to Group D rats without any DMH injection. The expression of the number and the area of aberrant crypt foci (ACF) positive for GST-P was maximum in DMH-treated group. Vanadium-treated rats significantly reduced (P < 0.001) the expression of GST-P positive ACF cells (by 71.13%) for the entire period of the study. Moreover the histopathological examination also showed that vanadium action could minimize the aberrant crypt foci (P < 0.001). Furthermore, vanadium supplementation also elevated SOD activities in both liver and colon (P < 0.01, P < 0.02 and P < 0.01, P < 0.02 respectively) when compared to their carcinogen counterparts. Our results confirm that vanadium is particularly effective in limiting the action of the carcinogen, thereby establishing its anticarcinogenicity in chemically induced rat colon carcinogenesis.
 ...
PMID:Vanadium inhibits placental glutathione S-transferase (GST-P) positive foci in 1,2-dimethyl hydrazine induced rat colon carcinogenesis. 1470 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>