Figure 1. Activity and toxicity of isoform-selective inhibitors of p110 in comparison with LY294002.
All inhibitors were screened against six glioma cell lines.
A and B: Representative results from U373MG cells treated with selective inhibitors of p110 catalytic subunits at doses indicated (6 hr). LY294002 served as positive control, and PIK-112 and PIK73 served as inactive controls. PI-103 showed the highest potency against p-Akt and was therefore further compared with LY294002. None of the compounds tested impacted activation of Erk kinase in a dose-dependent manner.
C and D: U87MG cells were treated with PI-103 (C) or LY294002 (D) for 24 hr. Graphs show measurements of cell death by LDH release (three 12-well plates per experimental point). Immunoblot shows levels of phosphorylated and total Akt proteins. PI-103 blocked p-Akt at dosages far below the toxic range, whereas toxic and efficacious dosages for LY294002 were overlapping.