ChemInform Abstract: NAD(P)H:quinone Oxidoreductase 1 (NQO1): Chemoprotection, Bioactivation, Gene Regulation and Genetic Polymorphisms

Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, Box C-238, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
Chemico-Biological Interactions (Impact Factor: 2.58). 05/2001; 129(1-2):77-97. DOI: 10.1016/S0009-2797(00)00199-X
Source: PubMed


NAD(P)H:quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase that is involved in chemoprotection and can also bioactivate certain antitumor quinones. This review focuses on detoxification reactions catalyzed by NQO1 and its role in antioxidant defense via the generation of antioxidant forms of ubiquinone and vitamin E. Bioactivation reactions catalyzed by NQO1 are also summarized and the development of new antitumor agents for the therapy of solid tumors with marked NQO1 content is reviewed. NQO1 gene regulation and the role of the antioxidant response element and the xenobiotic response element in transcriptional regulation is summarized. An overview of genetic polymorphisms in NQO1 is presented and biological significance for chemoprotection, cancer susceptibility and antitumor drug action is discussed.

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Article: ChemInform Abstract: NAD(P)H:quinone Oxidoreductase 1 (NQO1): Chemoprotection, Bioactivation, Gene Regulation and Genetic Polymorphisms

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    • "The enzyme catalyses the NADH or NADPH-dependent reduction of a variety of organic compounds, including quinones [78] [79] [80] [81] [82]. Its cellular role is not wholly clear, but it seems likely that NQO1 participates in the detoxification of xenobiotic compounds and also in the cycling of quinones in the cell [75]. Since it catalyses the two electron reduction of quinones directly to the corresponding quinols, it avoids the production of potentially damaging semiquinones [83]. "
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    ABSTRACT: Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors. VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structure-based drug design has identified NQO1 inhibitors which have potential for the development of anti-cancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.
    Current drug targets 07/2015; · 3.02 Impact Factor
    • "NQO1 metabolizes BL to highly unstable hydroquinone which is then oxidized back to semiquinone or quinone. All these reactions consume intracellular NADPH/NADH cell contents resulting in their exhaustion that may lead to ROS generation [21] [34] [37]. Since both molecules interfere with NAD metabolism, we therefore explored whether BL sensitized PK9 cells to APO866-induced cell death through exacerbation of NAD depletion. "
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    ABSTRACT: Pancreatic cancer (PC) is one of the most lethal human malignancies and a major health problem. Patients diagnosed with PC and treated with conventional approaches have an overall 5-year survival rate of less than 5%. Novel strategies are needed to treat this disease. Herein, we propose a combinatorial strategy that targets two unrelated metabolic enzymes overexpressed in PC cells: NAD(P)H:quinone oxidoreductase-1 (NQO1) and nicotinamide phosphoribosyl transferase (NAMPT) using β-lapachone (BL) and APO866, respectively. We show that BL tremendously enhances the antitumor activity of APO866 on various PC cell lines without affecting normal cells, in a PARP-1 dependent manner. The chemopotentiation of APO866 with BL was characterized by the following: (i) nicotinamide adenine dinucleotide (NAD) depletion; (ii) catalase (CAT) degradation; (iii) excessive H2O2 production; (iv) dramatic drop of mitochondrial membrane potential (MMP); and finally (v) autophagic-associated cell death. H2O2 production, loss of MMP and cell death (but not NAD depletion) were abrogated by exogenous supplementation with CAT or pharmacological or genetic inhibition of PARP-1. Our data demonstrates that the combination of a non-lethal dose of BL and low dose of APO866 optimizes significantly cell death on various PC lines over both compounds given separately and open new and promising combination in PC therapy. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.
    Biochimie 07/2015; 116. DOI:10.1016/j.biochi.2015.07.012 · 2.96 Impact Factor
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    • "NAD (P) H: quinone oxidoreductase 1 (NQO1), also known as DT-diaphorase, menadione reductase, or quinone reductase 1, is a cytoplasmic flavoenzyme encoded by a gene located on chromosome 16q22. NQO1 uses NADH or NADPH as substrates to directly reduce quinones to hydroquinones [7,8]. Functions of NQO1 include xenobiotic detoxification, superoxide scavenging and the maintenance of endogenous antioxidant vitamins [9]. "
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    ABSTRACT: quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing enzyme that detoxifies chemical stressors and antioxidants, providing cytoprotection in normal tissues. However, high-level expression of NQO1 has been correlated with numerous human malignancies, suggesting a role in carcinogenesis and tumor progression. This study aimed to explore the clinicopathological significance of NQO1 and as a prognostic determinant in breast cancer. A total of 176 breast cancer patients with strict follow-up, 45 ductal carcinoma in situ (DCIS), 22 hyperplasia and 52 adjacent non-tumor breast tissues were selected for immunohistochemical staining of NQO1 protein. Immunofluorescence staining was also performed to detect the subcellular localization of NQO1 protein in MCF-7 breast cancer cells. Eight fresh breast cancers paired with adjacent non-tumor tissues were quantified using real time RT-PCR (qRT-PCR) and western blot. The correlations between NQO1 overexpression and the clinical features of breast cancer were evaluated using chi-square test and Fisher's exact tests. The survival rate was calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazards models. NQO1 protein showed a mainly cytoplasmic staining pattern in breast cancer. The strongly positive rate of NQO1 protein was 61.9% (109/176) in breast cancer, and was significantly higher than in DCIS (31.1%, 14/45), hyperplasia tissues (13.6%, 3/22) and adjacent non-tumor tissues (13.5%, 7/52). High-level expression of NQO1 protein was correlated with late clinical stage, poor differentiation, lymph node metastasis, Her2 expression and disease-free and 10-year overall survival rates in breast cancer. Moreover, multivariate analysis suggested that NQO1 emerged as a significant independent prognostic factor along with clinical stage and Her2 expression status in patients with breast cancer. High-level expression of NQO1 appears to be associated with breast cancer progression, and may be a potential biomarker for poor prognostic evaluation of breast cancers.
    Journal of Experimental & Clinical Cancer Research 02/2014; 33(1):14. DOI:10.1186/1756-9966-33-14 · 4.43 Impact Factor
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