Oxaprozin: kinetic and dynamic profile in the treatment of pain

Kean, Walter F.

doi:10.1185/030079904125004420

Cited by 36 publications

(7 citation statements)

References 12 publications

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“…They exist as enantiomer pairs, and it is generally the S-enantiomer, but not the R -enantiomer, that possesses potent COX inhibitory activity (37). Some profens have been in use for roughly 30 years, most commonly as treatment for inflammation due to rheumatoid arthritis (38)(39)(40)(41)(42)(43). However, based on emerging studies associating NSAIDs with anticancer activity, various profens have been examined for their efficacy as chemopreventive and chemotherapeutic agents in a variety of cancer types (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

The Aryl Propionic AcidR-Flurbiprofen Selectively Induces p75NTR-Dependent Decreased Survival of Prostate Tumor Cells

et al. 2007

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Epidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer. In addition, some NSAIDs show anticancer activity in vitro. NSAIDs exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity; however, evidence suggests that COX-independent mechanisms mediate decreased prostate cancer cell survival. Hence, we examined the effect of selected aryl propionic acid NSAIDs and structurally related compounds on the decreased survival of prostate cancer cell lines PC-3, DU-145, and LNCaP by induction of the p75 NTR protein. p75NTR has been shown to function as a tumor suppressor in the prostate by virtue of its intracellular death domain that can initiate apoptosis and inhibit growth. The most efficacious compounds for induction of p75 NTR and decreased survival, in rank-order, were R-flurbiprofen, ibuprofen, oxaprozin, fenoprofen, naproxen, and ketoprofen. Because R-flurbiprofen and ibuprofen exhibited the greatest efficacy, we examined their dose-dependent specificity of induction for p75 NTR relative to other members of the death receptor family. Whereas treatment with R-flurbiprofen or ibuprofen resulted in a massive induction of p75 NTR protein levels, the expression of Fas, p55 TNFR , DR3, DR4, DR5, and DR6 remained largely unchanged. Moreover, transfection of either cell line before Rflurbiprofen or ibuprofen treatment with a dominant negative form of p75 NTR to antagonize p75 NTR activity or p75 NTR small interfering RNA to prevent p75 NTR protein expression rescued both cell lines from decreased survival. Hence, R-flurbiprofen and ibuprofen selectively induce p75 NTR -dependent decreased survival of prostate cancer cells independently of COX inhibition. [Cancer Res 2007;67(7):3254-62]

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Section: Discussionmentioning

confidence: 99%

The Aryl Propionic AcidR-Flurbiprofen Selectively Induces p75NTR-Dependent Decreased Survival of Prostate Tumor Cells

et al. 2007

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“…This finding is particularly interesting as it seems to indicate the potential ability of the anti‐inflammatory drug to induce MMP‐9 inhibition in vivo at therapeutic doses. This aspect must be taken on even greater value if we consider that, after its administration, oxaprozin can achieve high concentrations in synovial membrane (4–5 times higher than in plasma) with relevant inhibitory effects on enzymes degrading the ECM, mainly MMPs, that increase in the synovial fluid after IL‐I and TNFα induction (Kean, ).…”

Section: Resultsmentioning

confidence: 99%

Oxaprozin: A new hope in the modulation of matrix metalloproteinase 9 activity

2019

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Oxaprozin (4,5‐diphenyl‐2‐oxazolepropionic acid) is a non‐steroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory disorders is well known. The aim of this study was to investigate the ability of oxaprozin to modulate the activity of matrix metalloproteinase 9 (MMP‐9), a zinc‐dependent endopeptidase involved in a wide range of physiological and pathological events associated with extracellular matrix (ECM) remodelling. The interaction between oxaprozin and MMP‐9 was firstly investigated in silico by molecular docking and analysis with LIGPLOT software. Subsequently, the potential inhibitory activity of oxaprozin against MMP‐9 and the possible mechanism of the ligand–enzyme interaction were investigated in vitro. Taking into account the in silico findings, MMP‐9 can be considered a potential target of oxaprozin, which seems to be able to chelate the catalytic zinc ion through the nitrogen of the oxazole ring and the carboxylate moiety. Moreover, one of the phenyl rings interact with the S1′ inhibitor‐binding pocket through hydrophobic interaction. Gelatin zymography and enzymatic inhibition assay confirmed the potential role of oxaprozin as a competitive inhibitor of MMP‐9. These observations sound particularly interesting if we consider the pathological role of MMP‐9, especially evident in inflammatory conditions and cancer. This work may represent a starting point to improve the understanding of the role of oxaprozin, as well as its structural analogues, in modulating the MMP‐9 function.

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“…Oxaprozin has been shown as an effective drug in the clinical management of adult rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, soft tissue disorders, and postoperative dental pain [43]. In particular, oxaprozin treatment showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component in comparison with diclofenac [44].…”

Section: Discussionmentioning

confidence: 99%

Oxaprozin‐Induced Apoptosis on CD40 Ligand‐Treated Human Primary Monocytes Is Associated with the Modulation of Defined Intracellular Pathways

Montecucco

Bertolotto

Ottonello

et al. 2009

BioMed Research International

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The modulation of CD40L activity might represent a promising therapeutic target to reduce monocyte inflammatory functions in chronic diseases, such as rheumatoid arthritis. In the present study, we investigated the possible influence of nonsteroidal anti-inflammatory drugs (NSAIDs) on CD40L-induced monocyte survival. Monocytes were isolated from buffy coats by using Ficoll-Percoll gradients. Monocyte apoptosis was evaluated by fluorescence microscopy on cytopreps stained with acridine orange or using flow cytometry analysis of Annexin-V and Propidium Iodide staining. Akt and NF-κB activation was assessed using western blot. Caspase 3 activity was determined spectrophotometrically. Among different NSAIDs, only oxaprozin dose-dependently increased apoptosis of CD40L-treated monocytes. Oxaprozin pro-apoptotic activity was associated with the inhibition of CD40L-triggered Akt and NF-κB phosphorylation and the activation of caspase 3. In conclusion, our data suggest that oxaprozin-induced apoptosis in CD40L-treated human monocytes is associated with previously unknown cyclooxygenase (COX)-independent pathways. These intracellular proteins might be promising pharmacological targets to increase apoptosis in CD40L-treated monocytes.

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Oxaprozin: kinetic and dynamic profile in the treatment of pain

Cited by 36 publications

References 12 publications

The Aryl Propionic AcidR-Flurbiprofen Selectively Induces p75NTR-Dependent Decreased Survival of Prostate Tumor Cells

The Aryl Propionic AcidR-Flurbiprofen Selectively Induces p75NTR-Dependent Decreased Survival of Prostate Tumor Cells

Oxaprozin: A new hope in the modulation of matrix metalloproteinase 9 activity

Oxaprozin‐Induced Apoptosis on CD40 Ligand‐Treated Human Primary Monocytes Is Associated with the Modulation of Defined Intracellular Pathways

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