dicumarol and Breast-Neoplasms

dicumarol has been researched along with Breast-Neoplasms* in 11 studies

Other Studies

11 other study(ies) available for dicumarol and Breast-Neoplasms

ArticleYear
Mitochondrial "power" drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer.
    Oncotarget, 2017, Mar-02, Volume: 8, Issue:12

    Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007).

    Topics: Antineoplastic Agents, Hormonal; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dicumarol; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Glutamate-Cysteine Ligase; Humans; MCF-7 Cells; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Neoplasm Recurrence, Local; Prognosis; Proteomics; RNA, Messenger; Tamoxifen

2017
Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol.
    Clinical science (London, England : 1979), 2016, 12-01, Volume: 130, Issue:24

    Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-β (TGF-β)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

    Topics: Anticoagulants; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Dicumarol; Drug Resistance, Neoplasm; Female; Humans; Pregnancy-Specific beta 1-Glycoproteins; Taxoids; Transforming Growth Factor beta

2016
NADPH quinone oxidoreductase 1 mediates breast cancer cell resistance to thymoquinone-induced apoptosis.
    Biochemical and biophysical research communications, 2012, Sep-28, Volume: 426, Issue:3

    Thymoquinone (TQ), a bioactive component of black caraway seed (Nigella sativa) oil, is reported to have antineoplastic properties. In this study we investigated the effect of TQ on a panel of human breast cancer cell lines. Cell viability assays showed that TQ killed T-47D, MDA-MB-231, and MDA-MB-468 cells via p53-independent induction of apoptosis; however, MCF-7 cells were refractory to the cytotoxic action of TQ. Western Blot analysis showed that MCF-7 cells expressed high levels of cytoprotective NADPH quinone oxidoreductase 1 (NQO1), which was responsible for TQ-resistance since inhibition of NQO1 with dicoumarol rendered MCF-7 cells TQ-sensitive. These findings may be clinically important when considering TQ as a possible adjunct treatment for breast cancer since a high percentage of breast tumors express NQO1.

    Topics: Antineoplastic Agents; Apoptosis; Benzoquinones; Breast Neoplasms; Cell Line, Tumor; Dicumarol; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Humans; NAD(P)H Dehydrogenase (Quinone)

2012
3D-QSAR CoMFA studies on bis-coumarine analogues as urease inhibitors: a strategic design in anti-urease agents.
    Bioorganic & medicinal chemistry, 2008, Mar-15, Volume: 16, Issue:6

    A 3D-QSAR study has been performed on thirty (30) bis-coumarine derivatives to correlate their chemical structures with their observed urease inhibitory activity. Due to the absence of information on their active mechanism, comparative molecular field analysis (CoMFA) was used in the study. Two different properties: steric, electrostatic, assumed to cover the major contributions to ligand binding, were used to generate the 3D-QSAR model. Significant cross-validated correlation coefficients q(2) (0.558) and r(2) (0.992) for CoMFA were obtained, indicating the statistical significance of this class of compounds. The red electrostatic contour map highlighting those portion of compounds which may be interacting with nickel metal center in the active site of urease; while the blue contour map indicates positively charged groups in the ligands have improved biological activity and thus lower the IC(50)s. The steric contour map shows that bulkier substitutions at the 'R' position are detrimental to ligand receptor interaction. Actual urease inhibitory activities of this class and the predicted values were in good agreement with the experimental results. Moreover, from the contour maps, the key features vital to ligand binding have been identified, which are important for us to trace the important properties and gain insight into the potential mechanisms of intermolecular interactions between the ligand and receptor.

    Topics: Antineoplastic Agents; Breast Neoplasms; Coumarins; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Humans; Models, Molecular; Quantitative Structure-Activity Relationship; Urease

2008
Mitochondrial production of reactive oxygen species mediate dicumarol-induced cytotoxicity in cancer cells.
    The Journal of biological chemistry, 2006, Dec-08, Volume: 281, Issue:49

    Dicumarol is a naturally occurring anticoagulant derived from coumarin that induces cytotoxicity and oxidative stress in human pancreatic cancer cells (Cullen, J. J., Hinkhouse, M. M., Grady, M., Gaut, A. W., Liu, J., Zhang, Y., Weydert, C. J. D., Domann, F. E., and Oberley, L. W. (2003) Cancer Res. 63, 5513-5520). Although dicumarol has been used as an inhibitor of the two-electron reductase NAD(P)H:quinone oxidoreductase (NQO1), dicumarol is also thought to affect quinone-mediated electron transfer reactions in the mitochondria, leading to the production of superoxide (O2*-) and hydrogen peroxide (H(2)O(2)). We hypothesized that mitochondrial production of reactive oxygen species mediates the increased susceptibility of pancreatic cancer cells to dicumarol-induced metabolic oxidative stress. Dicumarol decreased clonogenic survival equally in both MDA-MB-468 NQO1(-) and MDA-MB-468 NQO1+ breast cancer cells. Dicumarol decreased clonogenic survival in the transformed fibroblast cell line IMRSV-90 compared with the IMR-90 cell line. Dicumarol, with the addition of mitochondrial electron transport chain blockers, decreased clonogenic cell survival in human pancreatic cancer cells and increased superoxide levels. Dicumarol with the mitochondrial electron transport chain blocker antimycin A decreased clonogenic survival and increased superoxide levels in cells with functional mitochondria but had little effect on cancer cells without functional mitochondria. Overexpression of manganese superoxide dismutase and mitochondrial-targeted catalase with adenoviral vectors reversed the dicumarol-induced cytotoxicity and reversed fluorescence of the oxidation-sensitive probe. We conclude mitochondrial production of reactive oxygen species mediates the increased susceptibility of cancer cells to dicumarol-induced cytotoxicity.

    Topics: Antineoplastic Agents; Breast Neoplasms; Catalase; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cell Survival; Dicumarol; Electron Transport; Female; Humans; Hydrogen Peroxide; Kinetics; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Pancreatic Neoplasms; Reactive Oxygen Species; Recombinant Proteins; Superoxide Dismutase; Tumor Stem Cell Assay; Uncoupling Agents

2006
NAD(P)H:Quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity.
    The Journal of biological chemistry, 2000, Feb-25, Volume: 275, Issue:8

    beta-Lapachone activates a novel apoptotic response in a number of cell lines. We demonstrate that the enzyme NAD(P)H:quinone oxidoreductase (NQO1) substantially enhances the toxicity of beta-lapachone. NQO1 expression directly correlated with sensitivity to a 4-h pulse of beta-lapachone in a panel of breast cancer cell lines, and the NQO1 inhibitor, dicoumarol, significantly protected NQO1-expressing cells from all aspects of beta-lapachone toxicity. Stable transfection of the NQO1-deficient cell line, MDA-MB-468, with an NQO1 expression plasmid increased apoptotic responses and lethality after beta-lapachone exposure. Dicoumarol blocked both the apoptotic responses and lethality. Biochemical studies suggest that reduction of beta-lapachone by NQO1 leads to a futile cycling between the quinone and hydroquinone forms, with a concomitant loss of reduced NAD(P)H. In addition, the activation of a cysteine protease, which has characteristics consistent with the neutral calcium-dependent protease, calpain, is observed after beta-lapachone treatment. This is the first definitive elucidation of an intracellular target for beta-lapachone in tumor cells. NQO1 could be exploited for gene therapy, radiotherapy, and/or chemopreventive interventions, since the enzyme is elevated in a number of tumor types (i.e. breast and lung) and during neoplastic transformation.

    Topics: Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Division; Cytochrome Reductases; Cytochrome-B(5) Reductase; Dicumarol; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Flow Cytometry; Humans; Models, Biological; NAD; NADH, NADPH Oxidoreductases; NADPH-Ferrihemoprotein Reductase; Naphthoquinones; Proteins; Quinone Reductases; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Vitamin K

2000
Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification. Mechanism of GST A1-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells.
    The Journal of biological chemistry, 1998, Aug-07, Volume: 273, Issue:32

    To examine the role of multidrug resistance protein 1 (MRP1) and glutathione S-transferases (GSTs) in cellular resistance to antineoplastic drugs, derivatives of MCF7 breast carcinoma cells were developed that express MRP1 in combination with one of three human cytosolic isozymes of GST. Expression of MRP1 alone confers resistance to several drugs representing the multidrug resistance phenotype, drugs including doxorubicin, vincristine, etoposide, and mitoxantrone. However, co-expression with MRP1 of any of the human GST isozymes A1-1, M1-1, or P1-1 failed to augment MRP1-associated resistance to these drugs. In contrast, combined expression of MRP1 and GST A1-1 conferred approximately 4-fold resistance to the anticancer drug chlorambucil. Expression of MRP1 alone failed to confer resistance to chlorambucil, showing that the observed protection from chlorambucil cytotoxicity was absolutely dependent upon GST A1-1 protein. Moreover, using inhibitors of GST (dicumarol) or MRP1 (sulfinpyrazone), it was shown that in MCF7 cells resistance to chlorambucil requires both intact MRP1-dependent efflux pump activity and, for full protection, GST A1-1 catalytic activity. These results are the first demonstration that GST A1-1 and MRP1 can act in synergy to protect cells from the cytotoxicity of a nitrogen mustard, chlorambucil.

    Topics: Antineoplastic Agents; Breast Neoplasms; Chlorambucil; Dicumarol; DNA-Binding Proteins; Drug Resistance, Multiple; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glutathione; Glutathione Transferase; Humans; Inactivation, Metabolic; Isoenzymes; Multidrug Resistance-Associated Proteins; MutS Homolog 3 Protein; Sulfinpyrazone; Transfection; Tumor Cells, Cultured

1998
The activity of xenobiotic enzymes and the cytotoxicity of mitoxantrone in MCF 7 human breast cancer cells treated with inducing agents.
    Chemico-biological interactions, 1995, Jul-14, Volume: 97, Issue:2

    This study investigated the effect of inducers on the major enzymes responsible for metabolising the quinone antitumor agent mitoxantrone, and on its cytotoxicity in MCF 7 human breast cancer cells. Four inducers were used: 1,2-benzanthracene (BA), phenobarbitone (PB); rifampicin (R) and dexamethasone (DEX). Of these, BA was the most effective, increasing cytochrome P450 dependent metabolism 64-fold and DT-diaphorase activity 1.6-fold. R did not cause an increase in any of the enzyme activities measured and, in fact inhibited glutathione peroxidase activity. PB and DEX increased NADPH cytochrome c reductase activity but had no effect on either DT-diaphorase or cytochrome P450 dependent activities. BA potentiated the cytotoxicity of mitoxantrone in terms of leakage of lactate dehydrogenase (LDH) activity and loss of reduced glutathione (GSH) and protein from cultures. PB had a smaller potentiating effect on cytotoxicity and DEX had no effect. Studies with the enzyme inhibitors, dicoumarol (inhibits DT-diaphorase) and metyrapone (inhibits cytochrome P450), indicate that at least two reactive species are involved in mitoxantrone cytotoxicity. One intermediate, formed by cytochrome P450, caused LDH leakage and GSH depletion. Formation of the second intermediate was catalysed by DT-diaphorase and this hydroquinone caused loss of intracellular protein and GSH. We propose that autooxidation of the hydroquinone resulting in generation of reactive oxygen species contributes to mitoxantrone cytotoxicity. Concomitant exposure to inducing agents may alter the cytotoxicity associated with many cytotoxic drugs, not just mitoxantrone, and this is an important consideration as many cytotoxics have a narrow therapeutic index.

    Topics: Benz(a)Anthracenes; Breast Neoplasms; Cell Death; Cytochrome P-450 Enzyme System; Dexamethasone; Dicumarol; Enzyme Induction; Female; Glutathione; Glutathione Peroxidase; Humans; L-Lactate Dehydrogenase; Metyrapone; Mitoxantrone; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Phenobarbital; Rifampin; Tumor Cells, Cultured; Xenobiotics

1995
Use of quinones in brain-tumor therapy: preliminary results of preclinical laboratory investigations.
    Journal of toxicology and environmental health, 1985, Volume: 16, Issue:5

    Failure of current chemotherapeutic agents to effectively treat human brain tumors has prompted the search for alternative regimens based on the inherent metabolic pathways of target cells. One way to accomplish this goal would be to design drugs in an inactive form, which upon entry into the cell would be transformed to a toxic metabolite by a naturally occurring pathway. One such pathway may be the reductive activation of naphthoquinones with one or two side chains capable of alkylation, such as 2,3-dibromomethyl-1,4-naphthoquinone (DBNQ). This reductive activation can be catalyzed by the flavoprotein DT-diaphorase [NAD(P)H:quinone oxidoreductase]. We have found that both rat 9L and some human brain-tumor cell lines contain very high levels of this enzyme and that halogenated dimethyl naphthoquinones, such as DBNQ, are highly toxic to these cells in vitro. Moreover, we have found that the cytotoxic effects of DBNQ on human tumor and murine bone marrow stem cells can be prevented or lessened by pretreatment of the cells with dicoumarol, a potent inhibitor of DT-diaphorase. Since dicoumarol does not cross the blood-brain barrier, the potential exists for human brain tumors to be destroyed with halogenated dimethylquinones and for peripheral host toxicity to be prevented by coadministration of dicoumarol.

    Topics: Animals; Bone Marrow Cells; Brain Neoplasms; Breast Neoplasms; Cell Survival; Cells, Cultured; Dicumarol; Glioma; Humans; Mice; NAD(P)H Dehydrogenase (Quinone); Quinone Reductases; Quinones; Rats

1985
Necrosis of the breast: a rare complication of anticoagulant therapy.
    American journal of surgery, 1966, Volume: 111, Issue:5

    Topics: Aged; Breast Diseases; Breast Neoplasms; Dicumarol; Female; Gangrene; Hemorrhage; Humans; Middle Aged; Necrosis; Pulmonary Embolism; Thrombophlebitis

1966
URETERIC OBSTRUCTION BY CLOT DURING ANTICOAGULANT TREATMENT.
    British medical journal, 1964, May-02, Volume: 1, Issue:5391

    Topics: Anticoagulants; Breast Neoplasms; Dicumarol; Hematuria; Humans; Mastectomy; Neoplasms; Thrombosis; Toxicology; Ureteral Obstruction; Urinary Catheterization; Vitamin K

1964
chemdatabank.com