Different PI 3-kinase inhibitors have distinct effects on endothelial permeability and leukocyte transmigration

Rob Cain, Bart Vanhaesebroeck, Anne J Ridley

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Endothelial cells play a central role in inflammatory responses, mediating leukocyte and solute traffic from blood vessels into the tissue, and are therefore key targets for anti-inflammatory therapies. Phosphoinositide 3-kinases (PI3Ks) are important signal transducers in inflammation and cancer, however there are 8 different PI3K catalytic isoforms, several of which have been shown to play distinct roles in cellular responses. Isoform-selective inhibitors have recently been described, but their effects on endothelial cell responses have not been compared. Here we compare the effects of the pan-PI3K inhibitor wortmannin with that of four more isoform-selective inhibitors, PI-103, TGX-221, AS604850 and IC87114, on endothelial cells stimulated with the pro-inflammatory cytokine TNFα. We find that PI-103 and wortmannin are most effective at reducing both endothelial permeability and leukocyte transendothelial migration (TEM), which correlates with a decrease in both the activity of the tyrosine kinase Pyk2 and its association with VE-cadherin. PI-103-related compounds are therefore likely to be good candidates for treating chronic inflammatory responses involving TNFα.
Original languageEnglish
Pages (from-to)1929-1936
Number of pages8
JournalInternational Journal of Biochemistry and Cell Biology
Issue number11
Publication statusPublished - Nov 2012


  • Adenine
  • Androstadienes
  • Antigens, CD
  • Cadherins
  • Capillary Permeability
  • Cell Membrane Permeability
  • Cell Shape
  • Class Ia Phosphatidylinositol 3-Kinase
  • Dioxoles
  • Endothelial Cells
  • Focal Adhesion Kinase 2
  • Furans
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Leukocytes
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein Binding
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Pyridines
  • Pyrimidines
  • Quinazolines
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Thiazolidinediones
  • Transendothelial and Transepithelial Migration
  • Tumor Necrosis Factor-alpha


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