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PMID: 20566897 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Blood ·Vol. 116 ·No. 15 ·2010-10-14 ·Pages 2732-41

Hu Y, Lu W, Chen G, Zhang H, Jia Y, Wei Y, Yang H, Zhang W, Fiskus W, Bhalla K, Keating M, Huang P, Garcia-Manero G

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.

MeSH Terms
Antioxidants/metabolism Base Sequence Cell Line, Tumor Cell Survival/drug effects DNA Primers/genetics Drug Resistance, Neoplasm Drug Synergism Enzyme Activation/drug effects Gene Expression Regulation, Neoplastic/drug effects HL-60 Cells Histone Deacetylase Inhibitors/administration & dosage,pharmacology Humans Hydroxamic Acids/administration & dosage,pharmacology Isothiocyanates/administration & dosage,pharmacology Leukemia/drug therapy,genetics,metabolism,pathology Leukemia, Myeloid/drug therapy,metabolism,pathology NADPH Oxidases/metabolism NF-E2-Related Factor 2/metabolism Oxidation-Reduction Reactive Oxygen Species/metabolism Tumor Cells, Cultured U937 Cells Vorinostat
Chemicals
Antioxidants DNA Primers Histone Deacetylase Inhibitors Hydroxamic Acids Isothiocyanates NF-E2-Related Factor 2 NFE2L2 protein, human Reactive Oxygen Species Vorinostat phenethyl isothiocyanate NADPH Oxidases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Hu Yumin
Departments of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Lu Weiqin
Chen Gang
Zhang Hui
Jia Yu
Wei Yue
Yang Hui
Zhang Wan
Fiskus Warren
Bhalla Kapil
Keating Michael
Huang Peng
Garcia-Manero Guillermo
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2009-11-256354
Published
2010-10-14
Epub
2010-00-21
Pages
2732-41
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC3324257
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA085563 · United States
NCI NIH HHS · R01 CA100428 · United States
External Links
PubMed source DOI: 10.1182/blood-2009-11-256354 PMC Full Text View journal details
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