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Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.
Morgan AJ, Kingsley PJ, Mitchener MM, Altemus M, Patrick TA, Gaulden AD, Marnett LJ, Patel S
(2018) ACS Chem Neurosci 9: 1552-1559
MeSH Terms: Animals, Arachidonic Acids, Brain, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Endocannabinoids, Esters, Female, Glycerides, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Transgenic, Monoacylglycerol Lipases, Neurons, Oxidation-Reduction, Prostaglandins
Show Abstract · Added October 8, 2018
Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
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18 MeSH Terms
Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors.
Uddin MJ, Crews BC, Xu S, Ghebreselasie K, Daniel CK, Kingsley PJ, Banerjee S, Marnett LJ
(2016) ACS Chem Biol 11: 3052-3060
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Crystallography, X-Ray, Cyclooxygenase 2 Inhibitors, Humans, Kinetics, Mice, Mice, Nude
Show Abstract · Added April 14, 2017
Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anticancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2's allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2 but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays.
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9 MeSH Terms
Cyclooxygenase-2 inhibition reduces stress-induced affective pathology.
Gamble-George JC, Baldi R, Halladay L, Kocharian A, Hartley N, Silva CG, Roberts H, Haymer A, Marnett LJ, Holmes A, Patel S
(2016) Elife 5:
MeSH Terms: Animals, Basolateral Nuclear Complex, Behavior, Animal, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Mice, Stress, Physiological
Show Abstract · Added March 14, 2018
Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.
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2 Members
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7 MeSH Terms
nido-Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase-2.
Neumann W, Xu S, Sárosi MB, Scholz MS, Crews BC, Ghebreselasie K, Banerjee S, Marnett LJ, Hey-Hawkins E
(2016) ChemMedChem 11: 175-8
MeSH Terms: Animals, Binding Sites, Boranes, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Dose-Response Relationship, Drug, Indomethacin, Mice, Models, Molecular, Molecular Structure, Sheep, Solubility, Structure-Activity Relationship
Show Abstract · Added February 22, 2016
Carbaboranes are increasingly studied as pharmacophores, particularly as replacements for aromatic systems. However, especially ortho-carbaborane is prone to degradation of the cluster, which hampers biological application. This study demonstrates that deboronation of the cluster may not only lead to a more active analogue, but can also improve the solubility and stability of a carbaborane-containing inhibitor. Notably, introduction of a nido-dicarbaborate cluster into the cyclooxygenase (COX) inhibitor indomethacin results in remarkably increased inhibitory potency and selectivity for COX-2 relative to the respective phenyl analogue. The first crystal structure of a carbaborane-containing inhibitor bound to COX-2 further reveals a novel binding mode for the inhibitor that is strikingly different from that of indomethacin. These results indicate that nido-dicarbaborate is a promising pharmacophore that exhibits properties which are also highly beneficial for its introduction into other inhibitor classes.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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13 MeSH Terms
Inhibition of 11β-Hydroxysteroid Dehydrogenase Type II Suppresses Lung Carcinogenesis by Blocking Tumor COX-2 Expression as Well as the ERK and mTOR Signaling Pathways.
Chang J, Xue M, Yang S, Yao B, Zhang B, Chen X, Pozzi A, Zhang MZ
(2015) PLoS One 10: e0127030
MeSH Terms: 11-beta-Hydroxysteroid Dehydrogenases, Animals, Apoptosis, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Corticosterone, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Endoplasmic Reticulum Stress, Extracellular Signal-Regulated MAP Kinases, Glycyrrhetinic Acid, Humans, Lung Neoplasms, Male, Mice, Inbred C57BL, Models, Biological, Signal Transduction, TOR Serine-Threonine Kinases
Show Abstract · Added October 30, 2016
Lung cancer is by far the leading cause of cancer death. Early diagnosis and prevention remain the best approach to reduce the overall morbidity and mortality. Experimental and clinical evidence have shown that cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) contributes to lung tumorigenesis. COX-2 inhibitors suppress the development and progression of lung cancer. However, increased cardiovascular risks of COX-2 inhibitors limit their use in chemoprevention of lung cancers. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11β-hydroxysteroid dehydrogenase type II (11ßHSD2)-mediated metabolism. We found that 11βHSD2 expression was increased in human lung cancers and experimental lung tumors. Inhibition of 11βHSD2 activity enhanced glucocorticoid-mediated COX-2 inhibition in human lung carcinoma cells. Furthermore, 11βHSD2 inhibition suppressed lung tumor growth and invasion in association with increased tissue active glucocorticoid levels, decreased COX-2 expression, inhibition of ERK and mTOR signaling pathways, increased tumor endoplasmic reticulum stress as well as increased lifespan. Therefore, 11βHSD2 inhibition represents a novel approach for lung cancer chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity and/or inhibits the ERK and mTOR signaling pathways.
1 Communities
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19 MeSH Terms
Targeted imaging of cancer by fluorocoxib C, a near-infrared cyclooxygenase-2 probe.
Uddin MJ, Crews BC, Ghebreselasie K, Daniel CK, Kingsley PJ, Xu S, Marnett LJ
(2015) J Biomed Opt 20: 50502
MeSH Terms: Animals, Cell Line, Tumor, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Female, Image Enhancement, Infrared Rays, Mice, Mice, Nude, Microscopy, Fluorescence, Molecular Diagnostic Techniques, Molecular Imaging, Molecular Probe Techniques, Neoplasms, Experimental, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added February 22, 2016
Cyclooxygenase-2 (COX-2) is a promising target for the imaging of cancer in a range of diagnostic and therapeutic settings. We report a near-infrared COX-2-targeted probe, fluorocoxib C (FC), for visualization of solid tumors by optical imaging. FC exhibits selective and potent COX-2 inhibition in both purified protein and human cancercell lines. In vivo optical imaging shows selective accumulation of FC in COX-2-overexpressing human tumor xenografts [1483 head and neck squamous cell carcinoma (HNSCC)] implanted in nude mice, while minimal uptake is detectable in COX-2-negative tumor xenografts (HCT116)or 1483 HNSCC xenografts preblocked with the COX-2-selective inhibitor celecoxib. Time course imaging studies conducted from 3 h to 7-day post-FC injection revealed a marked reduction in nonspecific fluorescent signals with retention of fluorescence in 1483 HNSCC tumors. Thus, use of FC in a delayed imaging protocol offers an approach to improve imaging signal-to-noise that should improve cancer detection in multiple preclinical and clinical settings.
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16 MeSH Terms
Action at a distance: mutations of peripheral residues transform rapid reversible inhibitors to slow, tight binders of cyclooxygenase-2.
Blobaum AL, Xu S, Rowlinson SW, Duggan KC, Banerjee S, Kudalkar SN, Birmingham WR, Ghebreselasie K, Marnett LJ
(2015) J Biol Chem 290: 12793-803
MeSH Terms: Animals, Catalytic Domain, Crystallography, X-Ray, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Mice, Mutation, Missense, Protein Binding, Static Electricity
Show Abstract · Added February 22, 2016
Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity of rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, and lumiracoxib) demonstrated a significant increase in potency and time dependence of inhibition against double tryptophan murine COX-2 mutants at the 89/90 and 89/119 positions. In contrast, the slow, time-dependent COX inhibitors (diclofenac, indomethacin, and flurbiprofen) were unaffected by those mutations. Further mutagenesis studies suggested that mutation at position 89 was principally responsible for the changes in inhibitory potency of rapid, reversible inhibitors, whereas mutation at position 90 may exert some effect on the potency of COX-2-selective diarylheterocycle inhibitors; no effect was observed with mutation at position 119. Several crystal structures with or without NSAIDs indicated that placement of a bulky residue at position 89 caused a closure of a gap at the lobby, and alteration of histidine to tryptophan at position 90 changed the electrostatic profile of the side pocket of COX-2. Thus, these two residues, especially Val-89 at the lobby region, are crucial for the entrance and exit of some NSAIDs from the COX active site.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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2 Members
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9 MeSH Terms
Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A.
Ra H, González-González E, Uddin MJ, King BL, Lee A, Ali-Khan I, Marnett LJ, Tang JY, Contag CH
(2015) Neoplasia 17: 201-7
MeSH Terms: Animals, Carcinoma, Basal Cell, Cyclooxygenase 2 Inhibitors, Indoles, Mice, Mice, SCID, Optical Imaging, Rhodamines, Skin Neoplasms
Show Abstract · Added February 22, 2016
Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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1 Members
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9 MeSH Terms
Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation.
Hermanson DJ, Gamble-George JC, Marnett LJ, Patel S
(2014) Trends Pharmacol Sci 35: 358-67
MeSH Terms: Animals, Cannabinoids, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Humans, Signal Transduction, Substrate Specificity
Show Abstract · Added June 1, 2014
Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of the canonical eCB inactivation pathways - fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-arachidonoylglycerol. We review here the experimental evidence that cyclooxygenase-2 (COX-2)-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of 'substrate-selective' COX-2 inhibitors (SSCIs) that prevent eCB inactivation by COX-2 without affecting prostaglandin (PG) generation from arachidonic acid (AA). Lastly, we review recent data on the potential therapeutic applications of SSCIs with a focus on neuropsychiatric disorders.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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2 Members
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7 MeSH Terms
Cyclooxygenase-2 catalysis and inhibition in lipid bilayer nanodiscs.
Orlando BJ, McDougle DR, Lucido MJ, Eng ET, Graham LA, Schneider C, Stokes DL, Das A, Malkowski MG
(2014) Arch Biochem Biophys 546: 33-40
MeSH Terms: Animals, Biocatalysis, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Enzyme Activation, Humans, Lipid Bilayers, Mice, Models, Molecular, Nanotechnology, Palmitic Acid, Phospholipids, Protein Conformation
Show Abstract · Added January 20, 2015
Cyclooxygenases (COX-1 and COX-2) oxygenate arachidonic acid (AA) to generate prostaglandins. The enzymes associate with one leaflet of the membrane bilayer. We utilized nanodisc technology to investigate the function of human (hu) COX-2 and murine (mu) COX-2 in a lipid bilayer environment. huCOX-2 and muCOX-2 were incorporated into nanodiscs composed of POPC, POPS, DOPC, or DOPS phospholipids. Size-exclusion chromatography and negative stain electron microscopy confirm that a single COX-2 homodimer is incorporated into the nanodisc scaffold. Nanodisc-reconstituted COX-2 exhibited similar kinetic profiles for the oxygenation of AA, eicosapentaenoic acid, and 1-arachidonoyl glycerol compared to those derived using detergent solubilized enzyme. Moreover, changing the phospholipid composition of the nanodisc did not alter the ability of COX-2 to oxygenate AA or to be inhibited by various nonselective NSAIDs or celecoxib. The cyclooxygenase activity of nanodisc-reconstituted COX-2 was reduced by aspirin acetylation and potentiated by the nonsubstrate fatty acid palmitic acid to the same extent as detergent solubilized enzyme, independent of phospholipid composition. The stabilization and maintenance of activity afforded by the incorporation of the enzyme into nanodiscs generates a native-like lipid bilayer environment to pursue studies of COX utilizing solution-based techniques that are otherwise not tractable in the presence of detergents.
Copyright © 2014 Elsevier Inc. All rights reserved.
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13 MeSH Terms