dicumarol has been researched along with Neoplasms* in 15 studies
3 review(s) available for dicumarol and Neoplasms
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NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places.
NAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease. Topics: Catalytic Domain; Dicumarol; Enzyme Inhibitors; Enzyme Stability; Flavin-Adenine Dinucleotide; Gene Expression; Humans; Models, Molecular; Mutation; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization | 2019 |
NAD(P)H:Quinone Oxidoreductase 1 (NQO1) as a Therapeutic and Diagnostic Target in Cancer.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron reductase responsible for detoxification of quinones and also bioactivation of certain quinones. It is abnormally overexpressed in many tumors and intimately linked with multiple carcinogenic processes. NQO1 is considered to be a cancer-specific target for therapy but currently available NQO1 inhibitors have not yet led to chemotherapeutic success. Utilization of NOQ1's ability to bioactivate chemotherapeutic quinones, however, has emerged as a promising selective anticancer therapy. On the basis of the different levels of NQO1 between cancer and normal cells, the catalytic property of NQO1 has recently been exploited to develop effective probes for cancer detection. This article summarizes the most significant advances concerning the discovery and development of NQO1 inhibitors, NQO1-directed chemotherapeutic quinones, and NQO1-activated optical probes, along with the prospects and potential obstacles in this research area. Topics: Antineoplastic Agents; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Quinones | 2018 |
6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling.
The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target. Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction | 2015 |
12 other study(ies) available for dicumarol and Neoplasms
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Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity.
Human NAD(P)H quinone oxidoreductase (DT-diaphorase, NQO1) exhibits negative cooperativity towards its potent inhibitor, dicoumarol. Here, we addressed the hypothesis that the effects of the two cancer-associated polymorphisms (p.R139W and p.P187S) may be partly mediated by their effects on inhibitor binding and negative cooperativity. Dicoumarol stabilized both variants and bound with much higher affinity for p.R139W than p.P187S. Both variants exhibited negative cooperativity towards dicoumarol; in both cases, the Hill coefficient ( Topics: Dicumarol; Enzyme Stability; Humans; Kinetics; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Niacinamide; Polymorphism, Genetic; Protein Binding; Quinone Reductases | 2019 |
Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands.
Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function. Topics: Binding Sites; Caco-2 Cells; Crystallography, X-Ray; Dicumarol; Enzyme Stability; Flavin-Adenine Dinucleotide; HCT116 Cells; HeLa Cells; Humans; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Polymorphism, Single Nucleotide; Protein Binding; Protein Conformation; Protein Multimerization | 2016 |
Pharmacological inhibitors of NAD(P)H quinone oxidoreductase, NQO1: structure/activity relationships and functional activity in tumour cells.
NAD(P)H quinone oxidoreductase (NQO1) has multiple functions in the cell including an ability to act as a detoxifying enzyme and as a protein chaperone. The latter property is particularly important in oncology as one of the client proteins of NQO1 is p53. The inhibitor, dicoumarol, is classically used to probe the biological properties of NQO1, but interpretation of enzyme function is compromised by the multiple "off-target" effects of this agent. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of recombinant human NQO1 have been identified (Nolan et al., J Med Chem 2009;52:7142-56) The purpose of the work reported here is to demonstrate the functional activity of these agents for inhibiting NQO1 in cells. To do this, advantage was taken of the NQO1-mediated toxicity of the chemotherapeutic drug EO9 (Apaziquone). The toxicity of this drug is substantially reduced when the function of NQO1 is inhibited and many of the coumarin-based compounds are more efficient than dicoumarol for inhibiting EO9 toxicity. The ability to do this appears to be related to their capacity to inhibit NQO1 in cell free systems. In conclusion, agents have been identified that may be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues. Topics: Antineoplastic Agents; Aziridines; Dicumarol; Humans; Indolequinones; NAD; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Proteins; Structure-Activity Relationship; Tumor Suppressor Protein p53 | 2010 |
Heat-induced up-regulation of NAD(P)H:quinone oxidoreductase potentiates anticancer effects of beta-lapachone.
The purpose of the present study was to evaluate the efficacy of mild hyperthermia to potentiate the anticancer effects of beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) by up-regulating NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells.. Effects of beta-lapachone alone or in combination with mild heating on the clonogenic survival of FSaII fibrosarcoma cells of C3H mice and A549 human lung tumor cells in vitro was determined. Effects of heating on the NQO1 level in the cancer cells in vitro were assessed using Western blot analysis for NQO1 expression, biochemical determination of NQO1 activity, and immunofluorescence microscopy for NQO1 expression. Growth of FSaII tumors in the hind legs of C3H mice was determined after treating the host mice with i.p. injection of 45 mg/kg beta-lapachone followed by heating the tumors at 42 degrees C for 1 hour every other day for four times.. Incubation of FSaII tumor cells and A549 tumor cells with beta-lapachone at 37 degrees C reduced clonogenic survival of the cells in dose-dependent and incubation time-dependent manner. NQO1 level in the cancer cells in vitro increased within 1 hour after heating at 42 degrees C for 1 hour and remained elevated for >72 hours. The clonogenic cell death caused by beta-lapachone increased in parallel with the increase in NQO1 levels in heated cells. Heating FSaII tumors in the legs of C3H mice enhanced the effect of i.p.-injected beta-lapachone in suppressing tumor growth.. We observed for the first time that mild heat shock up-regulates NQO1 in tumor cells. The heat-induced up-regulation of NQO1 enhanced the anticancer effects of beta-lapachone in vitro and in vivo. Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Combined Modality Therapy; Dicumarol; Enzyme Inhibitors; Humans; Hyperthermia, Induced; Mice; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Up-Regulation | 2005 |
[Incidence of tumors after treatment with oral anticoagulants].
Topics: Administration, Oral; Anticoagulants; Dicumarol; Embolism; Follow-Up Studies; Humans; Incidence; Neoplasms; Pulmonary Embolism; Risk Factors; Thrombosis; Time Factors; Warfarin | 2001 |
Menadione-induced cell degeneration is related to lipid peroxidation in human cancer cells.
The role of lipid peroxidation, intracellular glutathione and Ca2+ concentration in menadione-mediated toxicity was investigated in human hepatoma cell lines, Hep G2 and Hep 3B, and in human leukemia cell lines, CCRF-CEM and MOLT-3. Incubation of these cells with 80 microM menadione at 37 degrees C resulted in depletion of intracellular glutathione, increased intracellular Ca2+, and increased lipid peroxidation, events leading to cell degeneration. The sensitivity of these cells to menadione, in order, was: Hep G2 cells > Hep 3B cells > CCRF-CEM cells and MOLT-3 cells. The extent of menadione-induced lipid peroxidation in different cell types followed the same order as did their susceptibility to menadione-induced cell degeneration. The menadione-induced depletion in glutathione level was in the following sequence: Hep G2 cells > MOLT-3 and CCRF-CEM cells > Hep 3B cells. The extent of the menadione-induced increase in the intracellular Ca2+ concentration was: Hep G2 cells > Molt-3 cells > CCRF-CEM cells and Hep 3B cells. Pre-treatment of Hep G2 cells with 20 mM deferoxamine mesylate, an iron chelator, reduced both the menadione-induced cell degeneration and lipid peroxidation; however, it did not prevent the menadione-induced increase in intracellular Ca2+ nor the depletion of glutathione. These data suggest that menadione-induced cell degeneration is directly linked to lipid peroxidation, and that it is less related to the rise in intracellular Ca2+ and the depletion in glutathione content. Dicumarol (an inhibitor of DT diaphorase) enhanced the capacity of menadione to induce Hep 3B cell degeneration from 71.3% to 86.2% after 120 min of menadione treatment at 37 degrees C, but did not have this effect in Hep G2, CCRF-CEM or MOLT-3 cells. The activities of DT diaphorase were 52.4, 39.6, 1.5 and 1.8 nmol cytochrome c reduced/min/mg protein in Hep G2, Hep 3B, CCRF-CEM and MOLT-3 cells, respectively. The activity of DT diaphorase was much higher in Hep G2 cells than in the other cells. It seems that DT diaphorase may not, as suggested by others, protect against cell degeneration by quinones, such as menadione. Topics: Calcium; Carcinoma, Hepatocellular; Cell Death; Chelating Agents; Deferoxamine; Dicumarol; Glutathione; Glutathione Disulfide; Humans; Intracellular Fluid; Leukemia; Lipid Peroxidation; Liver Neoplasms; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Tumor Cells, Cultured; Vitamin K | 1998 |
Correctible complications of neoplastic diseases. IV. Autoimmune hemolytic anemia.
Topics: Anemia, Hemolytic, Autoimmune; Blood Transfusion; Dexamethasone; Dicumarol; Glucocorticoids; Hemodynamics; Heparin; Neoplasms; Prednisone; Spleen; Splenectomy; Thymectomy; Thymus Gland; Triamcinolone; Vincristine | 1971 |
URETERIC OBSTRUCTION BY CLOT DURING ANTICOAGULANT TREATMENT.
Topics: Anticoagulants; Breast Neoplasms; Dicumarol; Hematuria; Humans; Mastectomy; Neoplasms; Thrombosis; Toxicology; Ureteral Obstruction; Urinary Catheterization; Vitamin K | 1964 |
[MORTALITY IN FEMORAL NECK FRACTURES AND VALUE OF PREVENTIVE DICUMAROL TREATMENT].
Topics: 4-Aminobenzoic Acid; Aminobenzoates; Bronchopneumonia; Cerebral Hemorrhage; Cerebrovascular Disorders; Dicumarol; Dihydroergotoxine; Ergot Alkaloids; Femoral Neck Fractures; Fracture Fixation; Heparin; Mortality; Myocardial Infarction; Neoplasms; Phenindione; Preventive Medicine; Pulmonary Embolism; Surgical Procedures, Operative; Sweden; Thromboembolism | 1964 |
CANCER INCIDENCE AND MORTALITY IN PATIENTS HAVING ANTICOAGULANT THERAPY.
Topics: Acenocoumarol; Aged; Anticoagulants; Cerebrovascular Disorders; Coronary Disease; Dicumarol; Drug Therapy; Ethyl Biscoumacetate; Geriatrics; Humans; Incidence; Middle Aged; Mortality; Neoplasm Metastasis; Neoplasms; Pathology; Phenindione; Thromboembolism; Warfarin | 1964 |
Effect of heparin, protamine, dicoumarol, streptokinase and epsilon-amino-n-caproic acid on the growth of human cells in vitro.
Topics: Amino Acids; Caproates; Deoxyribonuclease I; Dicumarol; Heparin; Humans; In Vitro Techniques; Neoplasms; Protamines; Streptodornase and Streptokinase; Streptokinase; Tissue Culture Techniques | 1963 |
Acute myocardial infarction; detailed study of dicumarol therapy in 75 consecutive cases.
Topics: Anterior Wall Myocardial Infarction; Dicumarol; Heart Neoplasms; Humans; Infarction; Myocardial Infarction; Myocardium; Neoplasms | 1948 |