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)

Electrophiles generated during metabolic activation of carcinogens and reactive oxygen species formed from endogenous and exogenous sources might play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase II detoxifying enzymes to counteract the insults of these reactive intermediates is under intensive investigation. Nrf2, a bZIP transcription factor, plays a central role in the regulation of phase II genes by binding to the antioxidant response element (ARE) in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Phenethyl isothiocyanate (PEITC) is a promising chemopreventive agent that exerts its effects by induction of phase II enzymes via activation of Nrf2. In the present study, a transcriptional profile of liver of the wild-type (Nrf2+/+) and knock-out (Nrf2-/-) mice after treatments with vehicle or PEITC at 3 h and at 12 h was generated using the Affymetrix Mouse Genome 430 2.0 Array. Comparative analysis of gene expression changes between different treatment groups of wild-type and Nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2. These Nrf2-dependent and PEITC-inducible genes include known detoxication enzymes, as well as novel xenobiotic-metabolizing genes regulated by Nrf2 such as CYP 2c55, CYP 2u1 and aldehyde oxidase. Unexpected clusters included genes for heat shock proteins, ubiquitin/26 S proteasome subunits, and lipid metabolism molecules. Collectively, the identification of these genes not only provides novel insight into the effect of PEITC on global gene expression and chemoprevention, but also reveals the role of Nrf2 in those processes, which would confer cancer chemopreventive future.
 ...
PMID:Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. 1682 9

Typically chemopreventive agents either induce phase II detoxifying enzymes or inhibit the cytochrome P450 enzymes (CYPs) that are required for the metabolism of carcinogens. In this study, we isolated a coumarin compound, isoimperatorin from Poncirus trifoliata Raf., and studied its protective effects against aflatoxin B1 (AFB1)-induced cytotoxicity in H4IIE cells. Isoimperatorin (>0.3 microM) significantly inhibited the cytotoxic effect of AFB1. CDNB [1-chloro-2,4-dinitrobenzene; glutathine S-transferase (GST) subtype-non-specific] and NBD (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole; GSTalpha type-specific) assays revealed that isoimperatorin (0.3-3 microM) increased GST activity in a concentration-dependent manner. Western blot analyses using subtype-specific antibodies confirmed that GSTalpha protein, but not GSTmu or GSTpi, was induced in cells treated with isoimperatorin. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays revealed that GSTalpha induction by isoimperatorin is associated with Nrf2/ARE activation. Moreover, ethoxyresorufin-O-deethylase assays showed that isoimperatorin (2 microM) completely inhibited 3-methylchoranthrene-inducible CYP1A activity. These results indicate that isoimperatorin from Poncirus trifoliata Raf. possesses a potent hepatoprotective effect against AFB1, presumably through the induction of GSTalpha and the direct inhibition of CYP1A, and suggest that isoimperatorin should be considered a potential chemopreventive.
Carcinogenesis 2006 Dec
PMID:Potent protective effect of isoimperatorin against aflatoxin B1-inducible cytotoxicity in H4IIE cells: bifunctional effects on glutathione S-transferase and CYP1A. 1682 87

Chemopreventive agents induce a battery of genes whose protein products can protect cells from chemical-induced carcinogenesis. In this study, we isolated three different coumarins compounds (1; poncimarin, 2; heraclenol 3'-methyl ester and 3; oxypeucedanin methanolate) from Poncirus trifoliata Raf., and studied whether these compounds increase glutathione S-transferase (GST) expression and activity in the H4IIE cell-line (a rat hepatocyte cell line). CDNB (1-chloro-2,4-dinitrobenzene; GST subtype-nonspecific) and NBD (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole; GSTalpha-type-specific) assays revealed that compound 1 most potently increased GST enzyme activities. Western blot analysis using subtype-specific antibodies confirmed that these three coumarins also selectively increased GSTalpha-protein expression, and that compound 1 most actively induced GSTalpha. In contrast, the expressions of the GSTmu and GSTmu subtypes were not altered by these three coumarins. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays, revealed that GSTalpha-induction by compound 1 might be associated with Nrf2/ARE activation. These results suggest that these three coumarin compounds from Poncirus trifoliata Raf possess phase II enzyme inducible functions, and in particular, that poncimarin has chemopreventive potential.
 ...
PMID:Screening of potential chemopreventive compounds from Poncirus trifoliata Raf. 1702 Jan 59

Many studies on carcinogenesis carried out early in the last century are united on the consensus that cancer is a genetic disease. Cancer cells typically display gene dysfunction and endogenous or exogenous insults resulting in gene dysfunction are often carcinogenic. Recent advances in stem cell biology added the new concept that cancer originates from a single cancer-initiating cell. To understand the molecular basis of carcinogenesis from the beginning to the full acquirement of malignancy, factors concerned with carcinogenesis were categorized into three groups: those guarding and stabilizing genomes, those regulating cell proliferation, and those conferring resistance to various micro-environmental stresses. One example of particular interest is the Keap1-Nrf2 system since, according to recent studies, it has turned out to be ambivalent. Nrf2 heterodimerizes with small Maf protein to strongly activate transcription through the Maf recognition element (MARE) and Keap1 is an inhibitory regulator of Nrf2. The genes regulated by Nrf2 are very important for cellular protection of the genome from xenobiotic and oxidative stresses and, consequently, for preventing carcinogenesis. This implies that enhancing Nrf2 activity is a promising method for thwarting cancer. On the contrary, the constitutive activation of Nrf2 due to mutations in the keap1 gene is characteristically observed in lung cancer cells, suggesting that induced expression of Nrf2 target genes favors the prevalence of cancer cells.
 ...
PMID:Carcinogenesis and transcriptional regulation through Maf recognition elements. 1712 60

Placental glutathione transferase (GST-P) is specifically expressed during rat haptocarcinogenesis, and has been used as a reliable tumor marker for experimental hepatocarcinogenesis in the rat. The regulation of this tumor marker gene may be associated with the process of carcinogeneisis. By elucidating the mechanisms of such tumor marker gene expression, we may shed light on the molecular mechanisms of carcinogenesis. We analyzed the regulation of the GST-P gene and found that the strong enhancer element GPE1 (GST-P enhancer-1) specifically regulates the GST-P gene by interacting with specific transcription factors in normal liver and during hepatocarcinogenesis. In particular, C/EBPalpha was required for the suppression of GST-P gene in normal liver, whereas the Nrf2/MafK heterodimer was required for the activation of this gene during hepatocarcinogenesis. In this Mini-Review, we describe the positive and negative regulatory mechanisms in the pre-cancerous and normal liver, respectively.
 ...
PMID:Regulation of glutathione transferase P: a tumor marker of hepatocarcinogenesis. 1743 54

The Kelch ECH associating protein 1-nuclear factor-E2-related factor 2-antioxidant response element (Keap 1-Nrf2-ARE) signaling pathway regulates several protective mechanisms including expression of conjugating and antioxidative genes, antiinflammatory responses, the molecular chaperone/stress response system and the ubiquitin/proteasome system. The Nrf2-mediated response alters susceptibility to carcinogenesis, acute chemical toxicity, oxidative stress, asthma, acute inflammation, septic shock and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Studies using natural and synthetic chemical inducers that activate Nrf2 signaling have demonstrated protective efficacy in many animal models of disease. Conversely, studies in Nrf2-disrupted mice indicate they exhibit increased sensitivity to many of these diseases. Thus, activation of Keap1-Nrf2-ARE signaling constitutes a broad protective response, making Nrf2 and its interacting partners important targets for chemoprevention. However, additional studies are needed to characterize Keap1-Nrf2-ARE signaling in humans to further develop exceptionally potent activators of the pathway and further understand the potential consequences of altering this system.
 ...
PMID:Chemopreventive promise of targeting the Nrf2 pathway. 1744 Jun 34

Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2), a transcription factor that regulates inducible expression of detoxifying enzymes, is critical in preventing N-nitrosobutyl(4-hydroxybutyl)amine (BBN)-induced urinary bladder carcinogenesis. To explore whether Nrf2 and the tumor suppressor p53 cooperatively act in tumor prevention, we investigated the susceptibility of Nrf2-/-::p53+/- mice to BBN-induced urinary bladder carcinogenesis. The incidence of BBN-induced urinary bladder carcinoma was 63.0% in Nrf2-/- mice (P = 0.115), 75.8% in p53+/- mice (P < 0.01) and 89.6% in Nrf2-/-::p53+/- mice (P < 0.01) compared with 37.9% in wild-type. Higher incidence of carcinoma was observed in Nrf2-/-::p53+/- mice when compared with either Nrf2-/- (P < 0.01) or p53+/- mice (P = 0.382). Similarly, muscular invasive carcinoma incidence was higher in Nrf2-/-::p53+/- mice (62.0%) than either wild-type (6.9%, P < 0.01), p53+/- (38.0%, P = 0.110) or Nrf2-/- mice (3.7%, P < 0.01). Furthermore, urinary concentrations of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN, were only increased when Nrf2 but not p53 was disrupted. These results demonstrate that tumor susceptibility is synergistically exacerbated in Nrf2-/-::p53+/- mice due to poor detoxification and accelerated proliferation in comparison with either single mutant alone. BBN administration increased p53-mediated expression of p21, Mdm2 and Bax, and the inducible expression of p21 was significantly enhanced in Nrf2-/- mice. Conversely, modest increases in NAD(P)H dehydrogenase, quinone 1 (NQO1) and uridine diphosphate (UDP) glucuronosyltransferase 1A6 (UGT1A6) expression were observed in p53+/- compared with those of wild-type mice after BBN exposure. These results thus reveal potential interactions between p53 and Nrf2 and their gene batteries, and indicate that both factors cooperatively contribute to tumor prevention.
Carcinogenesis 2007 Nov
PMID:Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis. 1760 69

Prevention is one of the most important and promising strategies to control cancer. Many dietary bioactive compounds, mostly phytochemicals, have been found to decrease the risk of carcinogenesis. Modulating the metabolism and disposition pathways of carcinogens represents one of the major mechanisms by which dietary compounds prevent carcinogenesis. In the present review, the specific molecular targets of dietary compounds within carcinogen metabolism, including various enzymes and transporters and their regulatory signaling pathways, are briefly reviewed. The expression of phase I enzymes, which presumably mostly activate carcinogens, is mainly regulated by xenobiotics sensing nuclear receptors such as AhR, CAR, PXR, and RXR. On the other hand, phase II enzymes catalyze the conjugations of carcinogens and generally are transcriptionally controlled by the Nrf2/ARE signaling pathways. The Nrf2/ARE signaling pathway, which regulates the expression of many detoxifying enzymes, is a major target of dietary compounds. The final excretion of carcinogens and their metabolites is mediated by phase III transporters, which share many regulatory mechanisms with phase I/II enzymes. Indeed, the expression of metabolizing enzymes and transporters is often coordinately regulated. Besides transcriptional regulation, the activities of phase I/II enzymes and phase III transporters could be directly activated or inhibited by dietary compounds. Furthermore, genetic polymorphisms have profound effects on the individual response to dietary compounds. Finally, the effects of cancer prevention and the risk of carcinogenesis are determined by the network composed of known/unknown molecular targets and signaling pathways and its interaction with various xenobiotics, including carcinogens, drugs, and diet. With the rapid advances in the post genomic sciences, it could be possible to decipher this network and better predict the clinical outcomes of cancer prevention by dietary bioactive compounds.
 ...
PMID:Targeting carcinogen metabolism by dietary cancer preventive compounds. 1769

Cancer statistics from the American Cancer Society and other sources are a stark reminder of our failure to combat this deadly disease. Chemoprevention entails the use of specific naturally occurring dietary or synthetic agents to thwart cancer development and progression. Some of these agents are believed to do so by protecting the cells or tissues from the malicious attack of exogenous carcinogens and/or endogenous reactive oxygen/nitrogen species (RONS) by inducing several detoxifying/antioxidant enzymes that appear to form stable conjugates such as glutathione, glucuronides or sulfates thus rendering the carcinogenic species harmless. This process of inducing the cellular defense enzymes is believed to be mediated by the antioxidant response elements (ARE) within the promoter regions of these genes. Nrf2, a redox sensitive transcription factor has been documented to play a central role in ARE-driven gene expression. Nrf2, under normal unstimulated conditions, remains sequestered in the cytosol by Keap1. The putative chemopreventive agents disrupt the Nrf2-Keap1 association, thereby releasing Nrf2 which then translocates to the nucleus and drives the gene expression of detoxifying enzymes. The role of other transcription factors such as NF-kappaB and AP-1 in carcinogenesis is well established. By modulating the activity of these transcription factors and their upstream signaling molecules, naturally occurring dietary phytochemicals appear to cause apoptosis in abnormal cells that over-express these factors, thereby inhibiting the promotion and progression. This review discusses the most current and up to date understanding of the possible signaling mechanisms by which these naturally dietary phytochemicals can differentially modulate signal transduction cascades such that they can bring about apoptosis/cell death in abnormal cancer cells but at the same time induce defensive enzymes to protect against carcinogenesis in normal cells.
 ...
PMID:Anticarcinogenesis by dietary phytochemicals: cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa B and AP-1 in abnormal cancer cells. 1795 May 13

NO (nitric oxide) biology has provided the impetus for the development of anticancer agents based on their ability to release NO. NO-NSAIDs (NO-donating non-steroidal anti-inflammatory drugs), consisting of a conventional NSAID to which an NO-releasing moiety is covalently attached, are promising chemopreventive agents against cancer. Compared with their parent compounds, NO-NSAIDs are up to several hundred times more potent in inhibiting the growth of cancer cell lines and prevent colon and pancreatic cancer in animal models. Their chemopreventive effect is due to inhibition of proliferation, induction of cell death and inhibition of cell-cycle-phase transitions. NO-ASA (NO-aspirin), the best-studied NO-NSAID, induces oxidative stress in target cells. Major downstream signalling effects involve the Wnt, NOS2 (nitric oxide synthase 2), MAPK (mitogen-activated protein kinase), NF-kappaB (nuclear factor kappaB) and Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) pathways. NO-NSAIDs, particularly NO-ASA, appear to be safe compounds, as suggested by many animal and early human studies. An ongoing clinical trial is designed to determine whether NO-ASA can inhibit early stages of colon carcinogenesis in subjects at risk for colon cancer. It is clinical trials that will ultimately determine the role of NO-NSAIDs in cancer prevention and perhaps treatment.
 ...
PMID:Novel agents for cancer prevention based on nitric oxide. 1795 52


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