title: 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, including a majority of glutathione-associated enzymes as a cellular protective mechanism. Addition of β-phenylethyl isothiocyanate, a natural compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of vorinostat in leukemia cell lines and primary leukemia cells by inhibiting the cytoprotective antioxidant response. These results suggest that ROS plays an important role in action of vorinostat and that combination with a redox-modulating compound increases sensitivity to HDACIs and also overcomes vorinostat resistance. Such a combination strategy may be an effective therapeutic regimen and have potential clinical application in leukemia.
authors.affiliation: Departments of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Jia
authors.forename: Yue
authors.initials: Y
authors.lastname: Wei
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Wan
authors.initials: W
authors.lastname: Zhang
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D000077337:Vorinostat
chemical_list: D000975:Antioxidants; D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D000077337:Vorinostat; C058305:phenethyl isothiocyanate; D019255:NADPH Oxidases