Valdecoxib: the rise and fall of a COX-2 inhibitor

Atukorala, Inoshi; Hunter, David J.

doi:10.1517/14656566.2013.783568

Cited by 44 publications

(24 citation statements)

References 74 publications

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“…Indeed, both non-steroidal anti-inflammatory drugs (NSAIDs) and agents that selectively target COX2 (i.e., celecoxib, rofecoxib, valdecoxib) have been developed [24-26]. However, some COX2 inhibitors produce serious side effects such as gastrointestinal, cardiovascular, liver and kidney complications [27-29], resulting in their voluntary withdrawal from the market in some cases [30,31]. Therefore, exploiting α3β1 as a therapeutic target to down-regulate COX2 gene expression might circumvent certain side effects that have been associated with direct inhibitors of COX2.…”

Section: Introductionmentioning

confidence: 99%

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

et al. 2014

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BackgroundExpression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3β1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3β1 and COX2 by testing for their correlated expression among various forms of human breast cancer.MethodsImmunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman’s rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria.ResultsAlthough expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (rs = 0.49, p < 0.001, n = 59) and archived samples (rs = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage.ConclusionsCOX2 and α3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin α3β1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of α3β1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target α3β1, and that α3 expression might serve as an independent prognostic biomarker.

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Section: Introductionmentioning

confidence: 99%

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

et al. 2014

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“…Hence, more detailed analysis of docking poses and binding mechanisms was performed for the other studied COX isoform: COX-2. Diclofenac, indomethacin, celecoxib, and valdecoxib [46,47] were used as positive controls for COX-2 inhibition. The average binding energy predicted for decoys and known ligands into the COX-2 was −7.6 and −9.3 kcal/mol, respectively (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

et al. 2017

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Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.

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“…This so-called NSAID enteropathy continues to be greatly underrecognized and is subclinical in the vast majority of cases, and when there are symptoms (including iron-deficiency anemia, occult blood, diarrhea, hypoalbuminemia, and malabsorption), these are largely nonspecific. Unlike for NSAID gastropathy, there are no proven-effective preventive therapies [22,37,38].…”

Section: Gastrointestinal Injury Induced By Acetylsalicylic Acid Nonsmentioning

confidence: 99%

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

et al. 2015

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Bile acids are the end product of cholesterol metabolism. Synthesized in the liver, primary bile acids are secreted by hepatocytes and are transformed by intestinal microbiota into secondary bile acids. In addition to their role in cholesterol and lipid absorption, bile acids act as signaling molecules activating a family of nuclear and G-protein-coupled receptors collectively known as bile acid activated receptors (BARs). These receptors are expressed at high density in enterohepatic tissues, but their expression occurs throughout the body and their activation mediates regulatory functions of bile acids on lipids and glucose metabolism and immunity. In the gastrointestinal tract, BARs maintain intestinal integrity, and their deletion makes the intestine more susceptible to the damage caused by acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Deficiency in farnesoid X receptor and G-protein-coupled bile acid receptor 1 genes alters the expression/activity of cystathione c-lyase and endothelial nitric oxide synthase, two genes involved in the synthesis of hydrogen sulfide and nitric oxide, i.e., two gaseous mediators that have been shown to be essential in maintaining the intestinal homeostasis. In addition, farnesoid X receptor regulates the expression of transporters required for secretion of phospholipid by hepatocytes. Because phospholids attenuate intestinal injury caused by acetylsalicylic acid and NSAIDs, BAR agonism could be exploited to protect the intestinal mucosa against injury caused by anti-inflammatory medications. This approach might be useful in the prevention of so-called NSAID enteropathy, a common clinical condition occurring in long-term users of NSAIDs, which is not effectively prevented either by cotreatment with proton pump inhibitors or by the use of coxibs.

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Valdecoxib: the rise and fall of a COX-2 inhibitor

Cited by 44 publications

References 74 publications

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

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