PI3K AKT Signaling Pathways is an intracellular signalling pathway important in apoptosis

by Selleckchem | Jan 08 2013

Classical non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, PI3K AKT Signaling Pathways naproxen, and ibuprofen are known to reduce inflammation by blocking the formation of prostaglandins (PG) and thromboxanes through inhibition of cyclooxygenase (COX)-1 and COX-2 [1]. Part of their effectiveness and/or side effects stem from their ability to block the actions of COX-1 or COX-2 or both [2]. Reduced inflammation and enhanced therapeutic value of these inhibitors are thought to arise mainly from the inhibition of COX-2, while the sideeffects of gastric bleeding and ulceration arise due to the inhibition of COX-1 [3]. An increase in the expression of COX-2 in inflamed tissues is accompanied by an increase in its downstream product, PGE2, which sensitizes peripheral nociceptor terminals causing pain [4]. Highly COX-2 selective inhibitors, such as coxibs, possess anti-cancer and antiinflammatory activities [5]. Amongst these, celecoxib has gained considerable popularity for its dual role of selectively inhibiting Kinesin Spindle Protein COX-2 and effectively inhibiting the growth of adenomatous polyps in the colon [6].

A recent five-year efficacy and safety analysis of the adenoma prevention by celecoxib indicated that high-dose celecoxib (400 mg twice daily) was more effective than low dose celecoxib (200 mg twice daily) in reducing adenomas of the colon, but associated with an elevated risk for cardiovascular and thrombotic adverse events, particularly in patients with preexisting atherosclerotic heart disease [7]. Therefore, the ability to enhance the effect of celecoxib to promote its anti-proliferative and antiinflammatory TBC-11251 properties at concentrations with minimal or essentially no cardiovascular adversities would be highly desirable. We reasoned that enhancing the ability of celecoxib to inhibit COX-2 activity in addition to the inhibition of expression of COX-2 and other proinflammatory genes would potentially expand the spectrum of health benefits of celecoxib, particularly as an anti-cancer drug. Emerging evidence from epidemiological studies and clinical trials show the beneficial antiinflammatory effects of selenium (Se), an essential micronutrient. We have previously demonstrated that Se-supplementation of macrophages increased the expression of selenoproteins that effectively down-regulated PA-824 lipopolysaccharide (LPS)-induced COX-2 expression [8,9]).
The beneficial effects of Se, in the form of selenoproteins and novel organo-Se compounds, have been studied for their role as antioxidants, cytokine inducers, enzyme inhibitors, and antitumor agents [10?C16]. Along these lines, 1,4- phenylenebis(methylene)selenocyanate (p-XSC), a Se-derivative of benzylthiocyanate, displayed enhanced chemopreventive activity in rodents when compared to its precursor [17]. p-XSC effectively inhibited COX-2 expression via the inactivation of NF-??B [18], a redox-sensitive transcription factor that plays an important role in inflammatory process by regulating number of target genes such as COX-2, tumor necrosis factor (TNF)-??, and inducible nitric oxide synthase (iNOS). Along the same lines, recent studies by Desai et al (2010) [19], demonstrated that substitution of sulphur in PBIT (S,S??-(1,4-phenylenebis[1,2- ethanediyl])bisisothiourea), a well known iNOS inhibitor, with Se increased the proapoptotic ability of the isosteric analog towards many cancer cell lines by inhibiting PI3- kinase and Akt pathway. The concept of synthesis of Se-derivatives of celecoxib with anti-inflammatory and chemopreventive properties could, thus, represent an effective method to treat inflammatory processes, a hallmark of igf-1r tumorigenesis.
Based on our work with p-XSC and Se,Se??-(1,4- phenylenebis[1,2-ethanediyl])bisisoselenourea (PBISe), we hypothesized that inclusion of Se into celecoxib enhances the anti-inflammatory properties by inhibiting the enzymatic activity of COX-2 in addition to targeting cellular signaling pathways in immune cells. Although, clinical trials are in progress using celecoxib and Se yeast for the prevention of colon cancer [20], there are no biochemical studies that have characterized these Sederivatives of celecoxib. Here we report the synthesis of two Se-derivatives of celecoxib, namely, 4-(3-Selenocyanatomethyl-5-p-tolyl-1-yl)-benzenesulfonamide(selenocoxib-2) and 4-[5-(4-Methylseleanylmethyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl]- benezenesulfonamide (selenocoxib-3) and their characterization of the inhibition of COX-2 activity and modulation of NF-??B signaling axis in an in vitro macrophage model.