NSC-117079 at 30 μM induces neutrophil adhesion to plated fibrinogen from 9.0±2.4% to 27.0±8.0% and enhanced neutrophil adhesion caused by 50 ng/mL GM-CSF from 22.9±6.0% to 47.6±10.9%. Neutrophil adhesion is followed by neutrophil transendothelial migration. Results suggest that PHLPP inhibitor NSC-117079 is effective in preventing Akt from dephosphorylation in neutrophils, and Akt phosphatase PHLPP serves to attenuate neutrophil adhesion but not migration.
A single intraarticular injection of the Phlpp inhibitor NSC117079 attenuates mechanical allodynia and slows articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor seven weeks after injury maintain normal activity levels, while those in the control group travel shorter distances and are less active three months after the joint injury. NSC117079 also increases production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from osteoarthritis patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2 and PKC) in human articular chondrocytes.