Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isothiocyanate sulforaphane is an extensively studied cancer chemopreventive agent in human diet. In this study, the effects of sulforaphane (SFN) and its sulfide analog, erucin (ERN), have been examined on the induction of the phase II enzymes, quinine oxidoreductase (NQO1) and UDP-glucuronosyl transferase (UGT1A1), multidrug transporter (MRP2), cell cycle arrest and cell death in human colon adenocarcinoma Caco-2 cells. Additionally, the roles of PI3K/Akt and MEK/ERK signaling pathways have been assessed in these sulforaphane- and erucin-induced events. Although erucin and sulforaphane have similar IC50 values (21 and 23 microM after 72 h treatment), erucin was more effective in the induction of G2/M accumulation, depletion of mitochondrial potential, induction of cell death and mRNA induction of phase II enzymes and MRP2. Erucin (20 microM) induced the mRNAs of NQO1, UGT1A1 and MRP2 by 11.1-, 11.6- and 6.7-fold, whereas sulforaphane (20 microM) induced 3.3-, 5.3- and 2.2-fold, respectively. Both erucin and sulforaphane induced activation (phosphorylation) of ERK1/2 and Akt kinases but had no effect on JNK and p38 activation. Erucin-induced phase II enzyme transcriptions were decreased by PI3K and MEK1 inhibitors (LY294002 and PD98059), but the decreases in sulforaphane-induced transcription were less marked. Erucin induced a large increase in G2/M cell number than sulforaphane. The ability of kinase inhibitors to overcome G2/M block was low with the exception of PD98059 in sulforaphane-treated cells. Both, sulforaphane and erucin at high concentrations induced accumulation of sub-G1 cells, cell death and dissipation of mitochondrial membrane potential. Taken together, these results demonstrate that PI3K/Akt and MEK/ERK signals are important intracellular mediators in erucin- and sulforaphane-mediated phase II enzyme transcription and cell cycle arrest in Caco-2 cells.
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PMID:Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells. 1589 33

Adenocarcinoma of the breast is the most common cancer in women worldwide and its incidence is increasing in most countries. The present study was designed to evaluate the relationship between different clinical stages and menopausal status using the activity of phase I and II carcinogen-metabolising enzymes in breast cancer patients. Fifty breast cancer patients clinically categorized as stage I, II and III, and as pre- and postmenopausal were chosen for the study. The levels of cytochrome P450 and b(5) and the activity of glutathione S-transferase (GST), gamma-glutamyl transpeptidase (GGT), DT-diaphorase (DTD) and NADPH diaphorase in tumour tissues and adjacent normal tissues were estimated. Enhanced levels of cytochrome P450 and b(5) and phase II enzyme activity were observed in breast tumour tissues compared with the corresponding uninvolved adjacent tissues irrespective of clinical stage and menopausal status of the patients. The magnitude of the changes in phase I and II enzyme status was, however, more pronounced in stage I and in premenopausal patients than in stage II and III and postmenopausal patients respectively. Our results suggest that the balance between phase I carcinogen activation and phase II detoxification systems may play an important role in the development of breast tumours.
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PMID:Xenobiotic-metabolising enzymes in patients with adenocarcinoma of the breast: correlation with clinical stage and menopausal status. 1600 93

Modulation of drug metabolizing enzymes, leading to facilitated elimination of carcinogens represents a successful strategy for cancer chemoprevention. Nitric oxide-donating aspirin (NO-ASA) is a promising agent for the prevention of colon and other cancers. We studied the effect of NO-ASA on drug metabolizing enzymes in HT-29 human colon adenocarcinoma and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Min mice treated with NO-ASA for 3 weeks. In these cell lines, NO-ASA induced the activity and expression of NAD(P)H:quinone oxireductase (NQO) and glutathione S-transferase (GST). Compared with untreated Min mice, NO-ASA increased in the liver the activity (nmol/min/mg; mean+/-SEM for all) of NQO (85+/-6 versus 128+/-11, P<0.05) and GST (2560+/-233 versus 4254+/-608, P<0.005) and also in the intestine but not in the kidney; the expression of NQO1 and GST P1-1 was also increased. NO-ASA had only a marginal effect on P450 1A1 and P450 2E1, two phase I enzymes. The release of NO from NO-ASA, determined with a selective microelectrode was paralleled by the induction of NQO1 and abrogated by NO scavengers; an exogenous NO donor also induced the expression of NQO1. NO-ASA induced concentration-dependently the translocation of Nrf2 into the nucleus as documented by immunofluorescence and immunoblotting; this paralleled the induction of NQO1 and GST P1-1. Thus NO-ASA induces phase II enzymes, at least in part, through the action of NO that it releases and by modulating the Keap1-Nrf2 pathway; this effect may be part of its mechanism of action against colon and other cancers.
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PMID:NO-donating aspirin induces phase II enzymes in vitro and in vivo. 1626 95

Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.
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PMID:Novel lavendamycin analogues as antitumor agents: synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1. 1630 13

We investigated the effect of protein extract of Asterina pectinifera on the activity of 4 enzymes that may play a role in adenocarcinoma of the colon: quinone reductase (QR), glutathione S-transferase (GST), ornithine decarboxylase (ODC), and cyclooxygenase (COX)-2. QR and GST activity increased in HT-29 human colon adenocarcinoma cells increased that had been exposed to 4 concentrations of the protein extract (80, 160, 200, and 240 microg/mL). Additionally, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity decreased significantly in cells exposed to the extract in concentrations of 160 microg/mL (p<0.05), 200 microg/mL (p<0.005), and 240 microg/mL (p<0.005). TPA-induced COX-2 activity also decreased in cells exposed to extract concentrations of 10, 20, 40, and 60 microg/mL. COX-2 expression was also inhibited in cells exposed to this extract. These results suggest that this protein extract of A pectinifera has chemopreventive activity in HT-29 human colon adenocarcinoma cells, and therefore, may have the potential to function as a chemopreventive agent in human colorectal cancer.
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PMID:Chemopreventive effect of protein extract of Asterina pectinifera in HT-29 human colon adenocarcinoma cells. 1659 93

Neutrophil elastase (NE), a potent neutrophil inflammatory mediator, increases MUC5AC mucin gene expression through undefined pathways involving reactive oxygen species. To determine the source of NE-generated reactive oxygen species, we used pharmacologic inhibitors of oxidoreductases to test whether they blocked NE-regulated MUC5AC mRNA expression. We found that dicumarol, an inhibitor of the NADP(H):quinone oxidoreductase 1 (NQO1), inhibited MUC5AC mRNA expression in A549 lung adenocarcinoma cells and primary normal human bronchial epithelial cells. We further tested the role of NQO1 in mediating NE-induced MUC5AC expression by inhibiting NQO1 expression using short interfering RNA (siRNA). Transfection with siRNA specific for NQO1 suppressed NQO1 expression and significantly abrogated MUC5AC mRNA expression. NE treatment caused lipid peroxidation in A549 cells; this effect was inhibited by pretreatment with dicumarol, suggesting that NQO1 also regulates oxidant stress in A549 cells after NE exposure. NE exposure increased NQO1 protein and activity levels; NQO1 expression and activity were limited to the cytosol and did not translocate to the plasma membrane. Our results indicate that NQO1 has an important role as a key mediator of NE-regulated oxidant stress and MUC5AC mucin gene expression.
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PMID:Regulation of MUC5AC expression by NAD(P)H:quinone oxidoreductase 1. 1739 13

The ethanol extract of the aerial part of the Mongolian medicinal plant Saussurea salicifolia induced a dose-dependent cell growth inhibition in both human gastric adenocarcinoma AGS cells and mouse hepatoma Hepa 1c1c7 cells (IC(50)=30.22 and 116.96 mug/ml), respectively. The extract induced an apoptosis in AGS cells inference from the externalization of the phosphatidylserine, the increase of the sub G0/G1 content (%) and the apoptotic morphological changes including membrane blebbing, the formation of apoptotic bodies and chromatin condensation. In order to identify active substances causing the apoptosis, we further isolated major compounds present in Saussurea salicifolia and 7 compounds were isolated including a sesquiterpene lactone, cynaropicrin, 3 lignans (trachelogenin, matairesinol and arctigenin) and 3 lignan glycosides (tracheloside, matairesinoside and arctiin). In general the lignan aglycones were more cytotoxic than their lignan glycosides in both AGS cells and Hepa 1c1c7 cells. Cynaropicrin not only showed the most potent cytotoxicity among the 7 major compounds but also it induced an apoptosis and a weak G2/M arrest in AGS cells. Arctigenin had the second-best cytotoxicity among 7 major compounds, and induced an apoptosis. In order to evaluate the induction of the phase II detoxification enzyme, we measured the induction of quinone reductase activity of the extract, fractions and compounds in Hepa 1c1c7 cells. The ethyl acetate fraction and arctigenin showed the strongest cancer chemopreventive activity (chemoprevention index=9.88 and 7.57, respectively). These data suggest that the extract as well as the lignan compounds (especially arctigenin) originated from Saussurea salicifolia may be served as potential cancer chemopreventive agents for prevention or treatment of human cancers.
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PMID:The chemopreventive effects of Saussurea salicifolia through induction of apoptosis and phase II detoxification enzyme. 1805 25

Pancreatic ductal adenocarcinoma (PDA) is rarely curable due to regional/metastatic spread at diagnosis. Identification of molecular markers may enhance diagnosis and early detection of PDA. The 2-electron reductase, NAD(P)H:quinone oxidoreductase (NQO1) has been found to be overexpressed in many solid tumors including PDA, and may be a useful clinically relevant diagnostic marker of malignancy. For this study, we used 37 surgical resection cases: 24 PDAs and 13 benign pancreatic tissue specimens. An additional 16 specimens from pancreatic endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) were included as a pilot series. NQO1 was detected by avidin-biotin based immunohistochemical and immunocytochemical methods. Both staining intensity and proportion of NQO1 positive tumor cells were scored. Moderate to strong (2 to 3+) staining for NQO1 was detected in 22/24 (92%) surgically resected PDAs, 9/9 (100%) EUS-FNAs with malignant diagnoses, one cytologically atypical but not diagnostic for malignancy EUS-FNA, and 1/6 (17%) EUS-FNAs initially diagnosed as negative for malignancy. Subsequent histologic assessment confirmed malignancy in all 9 cytologically positive EUS-FNAs and in the atypical case. The NQO1 positive case initially diagnosed as negative for malignancy showed no evidence of carcinoma on subsequent tissue biopsy. NQO1 staining was also observed in some benign ducts/cells; however, correlation of NQO1 expression with cellular morphology assessment minimizes the risk of false positive diagnosis. NQO1 is consistently overexpressed in PDA. Although NQO1 is observed in some benign tissue components, this marker may be a clinically useful diagnostic adjunct for detection of PDA, independent of tumor grade/stage.
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PMID:NQO1 expression in pancreatic cancer and its potential use as a biomarker. 1809 24

A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.
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PMID:Lavendamycin antitumor agents: structure-based design, synthesis, and NAD(P)H:quinone oxidoreductase 1 (NQO1) model validation with molecular docking and biological studies. 1845 84

NAD(P)H:quinone oxidoreductase 1 null (NQO1(-/-)) mice exposed to 3 Gy of gamma-radiation showed an increase in neutrophils, bone marrow hypercellularity, and enlarged lymph nodes and spleen. The spleen showed disrupted follicular structure, loss of red pulp, and granulocyte and megakarocyte invasion. Blood and histologic analysis did not show any sign of infection in mice. These results suggested that exposure of NQO1(-/-) mice to gamma-radiation led to myeloproliferative disease. Radiation-induced myeloproliferative disease was observed in 74% of NQO1(-/-) mice as compared with none in wild-type (WT) mice. NQO1(-/-) mice exposed to gamma-radiation also showed lymphoma tissues (32%) and lung adenocarcinoma (84%). In contrast, only 11% WT mice showed lymphoma and none showed lung adenocarcinoma. Exposure of NQO1(-/-) mice to gamma-radiation resulted in reduced apoptosis in granulocytes and lack of induction of p53, p21, and Bax. NQO1(-/-) mice also showed increased expression of myeloid differentiation factors CCAAT/enhancer binding protein alpha (C/EBPalpha) and Pu.1. Intriguingly, exposure of NQO1(-/-) mice to gamma-radiation failed to induce C/EBPalpha and Pu.1, as was observed in WT mice. These results suggest that decreased p53/apoptosis and increased Pu.1 and C/EBPalpha led to myeloid hyperplasia in NQO1(-/-) mice. The lack of induction of apoptosis and differentiation contributed to radiation-induced myeloproliferative disease in NQO1(-/-) mice.
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PMID:Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to radiation-induced myeloproliferative disease. 1882 48


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