Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3-kinase-δ.

ABSTRACT: Corticosteroid insensitivity represents a major barrier to the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma. It is caused by oxidative stress, leading to reduced histone deacetylase-2 (HDAC2) function through activation of phosphoinositide-3-kinase-δ (PI3Kδ). The tricyclic antidepressant nortriptyline has been identified in high-throughput screens as an agent that increases corticosteroid responsiveness. The aim of this study was to identify the molecular mechanism whereby nortriptyline increases corticosteroid sensitivity. Phosphorylation of Akt, a footprint of PI3K activation, and HDAC activity were evaluated by Western blotting and fluorescent activity assay in U937 monocytic cells. Corticosteroid sensitivity was evaluated by the inhibition of tumor necros

SUBMITTER: Mercado N 

PROVIDER: S-EPMC3083104 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature