UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maintenance of cellular homeostasis is a critical survival trait when cells are exposed to electrophilic chemicals. Because conjugation and elimination of these toxins is dependent upon sequential and coordinated metabolic pathways, acquired resistance through a gradual adaptive response would rarely be expected to be the consequence of changes in one gene product. Human HT29 colon cancer cells chronically exposed to EA have acquired resistance to the drug. Commensurate with resistance, EA is more effectively conjugated to GSH and effluxed from the resistant cells. Using directed and random (differential display) approaches, a number of detoxification and/or protective gene products have been shown to be expressed at elevated levels. These include gamma-GCS (approximately 3-fold), GST-pi (approximately 3-fold), MRP (approximately 3-fold), NQO1 (approximately 3-fold), DDH (20-fold), and SSP 3521, a transcriptional regulator (approximately 3-fold). Multiple mechanisms contribute to these increases, including enhanced transcriptional rate and prolonged mRNA and protein half lives. Further indications for the involvement of transcriptional regulators is found in HL60 adriamycin-resistant cells which overexpress MRP, GST-pi and gamma-GCS and also have 15-20-fold more DNA-dependent protein kinase. It is possible that this enzyme serves as an early stress response gene which may activate downstream transcription factors. Intriguingly, the catalytic subunit of DNA-dependent protein kinase has a high avidity for [35S]azidophenacyl-GSH. High levels of GSH conjugates indicate cell stress and it would seem reasonable to speculate that DNA-dependent protein kinase may serve as a receiver and transmitter of signals which contribute to drug resistance and maintain cell viability.
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PMID:Coordinate changes in expression of protective genes in drug-resistant cells. 967 55

A network composed of activation and inactivation pathways to regulate mitomycin C (MMC) action is suggested to exist in human cancer cells. COLO201 colon cancer cells were stably transfected with human NQO1 cDNA that encodes NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD), and a clonal cell line with about 57-fold elevated DTD activity was obtained. Northern analysis revealed that expression of the NADPH:cytochrome P450 reductase (P450 reductase) gene was decreased in the transfectant, COLO201/NQO1, associated with the increase of NQO1 expression. Biochemical characterization of the cells showed a significant increase of the glutathione (GSH) content concomitantly with the decrease of the P450 reductase activity. As a result of these coordinated modulations, sensitivity of COLO201/NQO1 to MMC was not increased as compared to the parent cells. Analyses of inhibition by specific inhibitors of DTD, P450 reductase and glutathione S-transferase (GST) in 5 human colon cancer cell lines including the transfectant showed that DTD and P450 reductase play significant roles in MMC activation in cells with sufficiently high DTD activity and with marginal DTD activity, respectively. In contrast, GST appeared to participate in MMC inactivation in cells with a high level of GST activity. These results indicated that DTD, P450 reductase, GSH and GST may act together compensatively or competitively, depending on their levels in cells, to determine the cellular sensitivity to MMC.
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PMID:Regulatory network of mitomycin C action in human colon cancer cells. 1039 Oct 98

The present study used a rapid and single-step method for genotyping of NAD(P)H quinone oxidoreductase (NQO1) codon 609 polymorphism using real-time polymerase chain reaction (PCR)-analysis and subsequent melting curve analysis for the analysis of allelic distribution of NQO1. The design was a case control study of 323 Caucasians with colorectal cancer and 205 healthy controls. There was no difference in the frequencies of the mutated NQO1 allele (NQO1*2): 0.190 for control individuals and 0.195 for cancer patients, respectively (P=0.947). When this allelic distribution was further compared between non-smoking and smoking colorectal cancer patients, it appeared that the frequency of the wild-type allele NQO1*1 was higher in the smoking than in the non-smoking group [Odds ratio (OR), 0.434; 95% confidence interval (CI), 0.13-1.42]. This observation may suggest a protective role of the NQO1 wild-type allele in colon cancer susceptibility of individuals exposed to NQO1-inducing chemicals.
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PMID:NAD(P)H quinone oxidoreductase 1 codon 609 polymorphism and its association to colorectal cancer. 1066 83

DT-diaphorase is a two-electron reducing enzyme that is an important detoxifying enzyme and activator of bioreductive antitumor agents. Expression of the DT-diaphorase gene, NQO1, appears to be transcriptionally regulated, and the gene is induced by a wide variety of compounds. We showed that 1,2-dithiole-3-thione can selectively increase DT-diaphorase activity in human and murine tumors, and that this enhanced the antitumor activity of bioreductive antitumor agents. However, we found that DT-diaphorase activity was not increased in some human tumor cell lines after treatment with the inducer, and this appeared to be due to a lack of increased transcription. To determine if this lack of increased transcription was due to a mutation in the promoter region of the NQO1 gene in these cells, we sequenced approximately 2000 bases of the NQO1 promoter region from non-induced cells and compared these with sequences from human HT29 colon cancer cells, which showed significant increases in NQO1 transcription, and the sequence reported for human liver cells in Genbank. Sequence analysis showed no changes in the sequences of the major transcriptional elements, XRE, CAT box, ARE, AP1 site or AP2 site, in the tumor cells compared with the Genbank sequences. The only major change was a deletion of a 20 base repeat region approximately 400 bases 5' to the XRE element in all the cells, including the HT29 cells, compared with the sequence reported in Genbank. There were also several insertions of a single base in various parts of the sequences which occurred in most, or all, of the cell lines compared with the reported sequence, and a small number of single base changes, insertions or deletions that occurred in a single cell line. However, these changes did not appear to correlate with differences in induced transcription of the NQO1 gene. These results suggest that the differences in transcription of the NQO1 gene after treatment with DT-diaphorase inducers was not due to alterations in the promoter region of the gene.
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PMID:Lack of NQO1 induction in human tumor cells is not due to changes in the promoter region of the gene. 1189 33

Phase II detoxifying enzymes like NAD(P)H (quinone acceptor)oxidoreductase1 (NQO1), glutathione S-transferases (GST), and UDP-glucuronyltransferases (UGT) may play an important role in preventing carcinogen-induced cancers. Inducers of these enzymes have been shown to inhibit carcinogen-induced colon tumors in rat and mouse models. However, it has not been clearly demonstrated that NQO1 contributes to this effect. We examined the effect of NQO1 inducers on colon carcinogenesis using an aberrant crypt foci (ACF) rat model. Sprague-Dawley rats were fed control diet or diet containing 400 ppm dimethyl fumarate or 200 ppm oltipraz for 7 days, and Phase II enzymes in rat colon and liver were measured. Dimethyl fumarate significantly increased NQO1 and GST activities in colon and liver but did not increase UGT activities in these tissues. In contrast, oltipraz significantly increased NQO1 activities in colon and liver and produced a small increase in GST activity in the liver but did not increase GST activity in the colon or UGT activities in the liver or colon. Sprague Dawley rats were fed control diet or diet containing 200 ppm oltipraz and then treated with the carcinogens azoxymethane or methyl nitrosourea. Both carcinogens produced ACF in all of the rat colons, but rats fed oltipraz diet had significantly fewer ACF than those fed control diet. This protective effect was reversed in rats treated with the NQO1 inhibitor, dicoumarol. However, treatment with oltipraz did not alter the distribution of crypt multiplicities in the ACF. These studies demonstrated that induction of NQO1 plays a significant role in inhibiting initiation of carcinogen-induced ACF in Sprague-Dawley rats. This provides the first direct evidence that NQO1 may play a role in preventing colon cancer. The study also found that oltipraz added to the diet of Sprague-Dawley rats selectively increased NQO1 activity in colon mucosa with no increase in GST and UGT activities in these tissues. Thus, this model will be useful for further investigating the role of NQO1 in prevention of colon cancer.
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PMID:Induction of NAD(P)H quinone: oxidoreductase1 inhibits carcinogen-induced aberrant crypt foci in colons of Sprague-Dawley rats. 1281 4

Chemoprevention by the dithiolethione analogue oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) may occur through several mechanisms, among them stimulation of detoxication activity. The phase II detoxication enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2) also known as quinone reductase (QR) is well established to undergo transcriptional activation following oltipraz treatment of colon cancer cells in culture. Promoter analysis of the QR gene in oltipraztreated cells reveals the involvement of both the AP-1 and NF-kappaB elements in the response. The emerging role of NF-kappaB in cell survival prompted a fuller analysis of effects of oltipraz on this pathway. Oltipraz treatment of both HCT116 and HT29 cells results in the induction of proteins involved in both pathways of NF-kappaB activation, including p65, IkappaB kinase alpha (IKKalpha), IkappaB kinase beta (IKKbeta), and NF-kappaB-inducing kinase (NIK). IkappaBalpha total protein levels were unchanged, but phosphorylation of the inhibitor was also induced in both lines. Electrophoretic mobility shift assay (EMSA) analysis confirmed induction of protein binding to a consensus NF-kappaB element, and transcriptional activation was further confirmed using a reporter construct. Transcriptional activation of QR was decreased in a dose-dependent manner by dominant-negative NF-kappaB in both cell lines. The molecular mechanism that triggers IKK activation in response to oltipraz was also examined using inhibitory constructs of NIK and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). We found that both MEKK3 and NIK exert effects on IKKalpha/beta activation, but through different pathways. Furthermore, the receptor-interacting protein (RIP) was found to interact strongly with MEKK3 during oltipraz-induced NF-kappaB signaling, implying a role for tumor necrosis factor receptor signaling in the action of oltipraz. These results implicate a novel signaling pathway for the action of oltipraz in QR gene regulation.
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PMID:NF-kappaB activation by the chemopreventive dithiolethione oltipraz is exerted through stimulation of MEKK3 signaling. 1504 5

NQO1 is a reductive enzyme that is important for the activation of many bioreductive agents and is a target for an enzyme-directed approach to cancer therapy. It can be selectively induced in many tumor types by a number of compounds including dimethyl fumarate and sulforaphane. Mitomycin C is a bioreductive agent that is used clinically for treatment of solid tumors. RH1 (2,5-diaziridinyl-3-(hydroxymethyl)- 6-methyl-1,4-benzoquinone) is a new bioreductive agent currently in clinical trials. We have shown previously that induction of NQO1 can enhance the antitumor activity of mitomycin C in tumor cells in vitro and in vivo. As RH1 is activated selectively by NQO1 while mitomycin C is activated by many reductive enzymes, we investigated whether induction of NQO1 would produce a greater enhancement of the antitumor activity of RH1 compared with mitomycin C. HCT116 human colon cancer cells and T47D human breast cancer cells were incubated with or without dimethyl fumarate or sulforaphane followed by mitomycin C or RH1 treatment, and cytotoxic activity was measured by a clonogenic (HCT116) or MTT assay (T47D). Dimethyl fumarate and sulforaphane treatment increased NQO1 activity by 1.4- to 2.8-fold and resulted in a significant enhancement of the antitumor activity of mitomycin C, but not of RH1. This appeared to be due to the presence of a sufficient constitutive level of NQO1 activity in the tumor cells to fully activate the RH1. Mice were implanted with HL60 human promyelocytic leukemia cells, which have low levels of NQO1 activity. The mice were fed control or dimethyl fumarate-containing diet and were treated with RH1. NQO1 activity in the tumors increased but RH1 produced no antitumor activity in mice fed control or dimethyl fumarate diet. This is consistent with a narrow window of NQO1 activity between no RH1 activation and maximum RH1 activation. This study suggests that selective induction of NQO1 in tumor cells is not likely to be an effective strategy for enhancing the antitumor activity of RH1. In addition, we found that RH1 treatment produced significant leukopenia in mice that may be of concern in the clinic. These results suggest that the ease of reduction of RH1 by NQO1 makes it a poor candidate for an enzyme-directed approach to cancer therapy.
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PMID:Effect of NQO1 induction on the antitumor activity of RH1 in human tumors in vitro and in vivo. 1587 30

RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), which is currently in clinical trials, is a diaziridinyl benzoquinone bioreductive anticancer drug that was designed to be activated by the obligate two-electron reductive enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). In this electron paramagnetic resonance (EPR) study we showed that RH1 was reductively activated by the one-electron reductive enzyme NADPH cytochrome P450 reductase and by a suspension of HCT116 human colon cancer cells to yield a semiquinone free radical. As shown by EPR spin trapping experiments RH1 was reductively activated by cytochrome P450 reductase and underwent redox cycling to produce damaging hydroxyl radicals in reactions that were both H2O2- and iron-dependent. Thus, reductive activation by cytochrome P450 reductase or other reductases to produce a semiquinone that can redox cycle to produce damaging hydroxyl radicals and/or DNA-reactive alkylating species may contribute to the potent cell growth inhibitory effects of RH1. These results also suggest that selection of patients for treatment with RH1 based on their expression levels of NQO1 may be problematic.
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PMID:The reductive activation of the antitumor drug RH1 to its semiquinone free radical by NADPH cytochrome P450 reductase and by HCT116 human colon cancer cells. 1701 78

Colon cancer is one of the most common cancers in North America and generally develops from colonic epithelial cells following initiation by carcinogens. We have shown that the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1) contributes to the inhibition of carcinogen-induced colon cancer in rats at both the initiation and postinitiation stages. An inactivating polymorphism at base 609 of the NQO1 gene, (609)C (NQO1 *1) --> (609)T (NQO1 *2), occurs at high frequency in the human population. Thus, we carried out a case-control study to determine if this polymorphism is associated with an increased risk of developing colon cancer. A total of 298 patients with colon cancer and 349 healthy controls matched for age, gender, and ethnic origin were enrolled in the study. There was an increased incidence of the NQO1 *2/*2 genotype in patients with colon cancer, with a gender and age-adjusted odds ratio of 2.68 (95% confidence intervals, 1.14-6.28). However, the incidence of the NQO1 *1/*2 genotype was not increased in patients with colon cancer compared with controls. When the patient and control groups were stratified by tobacco and alcohol use, the incidences of the NQO1 *2/*2 genotype were increased in patients with colon cancer for tobacco and alcohol users and nonusers, suggesting that there is no interaction between the NQO1 base 609 polymorphism and tobacco or alcohol use. These results strongly suggest that NQO1 plays a significant role in preventing the development of colon cancer, and individuals with an NQO1 *2/*2 genotype are at an increased risk of developing this disease.
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PMID:A NAD(P)H:quinone oxidoreductase 1 polymorphism is a risk factor for human colon cancer. 1716 65

Ca(2+) and the cell-surface calcium sensing receptor (CaSR) constitute a novel and robust ligand/receptor system in regulating the proliferation and differentiation of colonic epithelial cells. Here we show that activation of CaSR by extracellular Ca(2+) (or CaSR agonists) enhanced the sensitivity of human colon carcinoma cells to mitomycin C (MMC) and fluorouracil (5-FU). Activation of CaSR up-regulated the expression of MMC activating enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO-1) and down-regulated the expression of 5-FU target, thymidylate synthase (TS) and the anti-apoptotic protein survivin. Cells that were resistant to drugs expressed little or no CaSR but abundant amount of survivin. Disruption of CaSR expression by shRNA targeting the CaSR abrogated these modulating effects of CaSR activation on the expression of NQO1, TS, survivin and cytotoxic response to drugs. It is concluded that activation of CaSR can enhance colon cancer cell sensitivity to MMC and 5-FU and can modulate the expression of molecules involved in the cellular responses to these cytotoxic drugs.
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PMID:Calcium and calcium sensing receptor modulates the expression of thymidylate synthase, NAD(P)H:quinone oxidoreductase 1 and survivin in human colon carcinoma cells: promotion of cytotoxic response to mitomycin C and fluorouracil. 1861 19

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