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Given this, we hypothesized that inhibitors of PI3K activation would demonstrate anti-inflammatory potential. Accordingly, we studied the effects of a preferential p110\u03b1\/\u03b3 PI3K inhibitor (compound 8C; PIK-75) in inflammation-based assays. Mechanism-based assays utilizing human cells revealed that PIK-75-mediated inhibition of PI3K activation is associated with dramatic suppression of downstream signaling events, including AKT phosphorylation, IKK activation, and NF-\u03baB transcription. Cell-based assays revealed that PIK-75 potently and dose dependently inhibits in vitro and in vivo production of TNF-\u03b1 and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion. Most importantly, PIK-75, when administered orally in a therapeutic regimen, significantly suppresses the macroscopic and histological abnormalities associated with dextran sulfate sodium-induced murine colitis. The efficacy of PIK-75 in attenuating experimental inflammation is mediated, at least in part, due to the downregulation of pertinent inflammatory mediators in the colon. Collectively, these results provide first evidence that PIK-75 possesses anti-inflammatory potential. Given that PIK-75 is known to exhibit anti-cancer activity, the findings from this study thus reinforce the cross-therapeutic functionality of potential drugs.<\/jats:p>","DOI":"10.1152\/ajpcell.00461.2009","type":"journal-article","created":{"date-parts":[[2010,1,21]],"date-time":"2010-01-21T03:39:41Z","timestamp":1264045181000},"page":"C929-C941","source":"Crossref","is-referenced-by-count":41,"title":["A preferential p110\u03b1\/\u03b3 PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-\u03baB-dependent manner"],"prefix":"10.1152","volume":"298","author":[{"given":"Nilesh M.","family":"Dagia","sequence":"first","affiliation":[{"name":"Departments of 1Pharmacology,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gautam","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Departments of 1Pharmacology,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Divya 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