title: A preferential p110alpha/gamma PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-kappaB-dependent manner.
abstract: A promising therapeutic approach to diminish pathological inflammation is to inhibit the increased production and/or biological activity of proinflammatory cytokines (e.g., TNF-alpha, IL-6). The production of proinflammatory cytokines is controlled at the gene level by the activity of transcription factors, such as NF-kappaB. Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is known to induce the activation of NF-kappaB. Given this, we hypothesized that inhibitors of PI3K activation would demonstrate anti-inflammatory potential. Accordingly, we studied the effects of a preferential p110alpha/gamma 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-kappaB transcription. Cell-based assays revealed that PIK-75 potently and dose dependently inhibits in vitro and in vivo production of TNF-alpha 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.
authors.affiliation: Dept. of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Off. Western Express Highway, Goregaon (East), Mumbai 400063, Maharashtra, India. nilesh.dagia@piramal.com
authors.forename: Nilesh M
authors.initials: NM
authors.lastname: Dagia
authors.forename: Gautam
authors.initials: G
authors.lastname: Agarwal
authors.forename: Divya V
authors.initials: DV
authors.lastname: Kamath
authors.forename: Anshu
authors.initials: A
authors.lastname: Chetrapal-Kunwar
authors.forename: Ravindra D
authors.initials: RD
authors.lastname: Gupte
authors.forename: Mahesh G
authors.initials: MG
authors.lastname: Jadhav
authors.forename: Shruta S
authors.initials: SS
authors.lastname: Dadarkar
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Trivedi
authors.forename: Asha A
authors.initials: AA
authors.lastname: Kulkarni-Almeida
authors.forename: Firuza
authors.initials: F
authors.lastname: Kharas
authors.forename: Lyle C
authors.initials: LC
authors.lastname: Fonseca
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.forename: Mandar R
authors.initials: MR
authors.lastname: Bhonde
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy / Q000276:immunology; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006835:Hydrazones / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019040:E-Selectin; D004791:Enzyme Inhibitors; D006835:Hydrazones; D051550:I-kappa B Kinase; D018836:Inflammation Mediators; D018799:Intercellular Adhesion Molecule-1; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021122:Protein Subunits; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000093242:Interleukin-6 Inhibitors; C549211:PIK 75