Overcoming resistance to histone deacetylase inhibitors in human leukemia with the redox modulating compound β-phenylethyl isothiocyanate.

ABSTRACT: Mechanisms of action and resistance of histone deacetylase inhibitors (HDACIs) are not well understood. A gene expression analysis performed in a phase 1 trial of vorinostat in leukemia indicated that overexpression of genes involved in antioxidant defense was associated with clinical resistance. We hypothesized that nonepigenetic mechanisms may be involved in resistance to HDACI therapy in leukemia. Here we confirmed up-regulation of a series of antioxidants in a pan-HDACI-resistant leukemia cell line HL60/LR. Vorinostat induced reactive oxygen species (ROS) through nicotinamide adenine dinucleotide phosphate oxidase in leukemia cells. An increase in ROS resulted in translocation of nuclear factor E2-related factor 2 from cytosol to nucleus, leading to up-regulation of antioxidant genes,

SUBMITTER: Hu Y 

PROVIDER: S-EPMC3324257 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature