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

Yumin Hu, Weiqin Lu, Gang Chen, Hui Zhang, Yu Jia, Yue Wei, Hui Yang, Wan Zhang, Warren Fiskus, Kapil Bhalla, Michael Keating, Peng Huang, Guillermo Garcia-Manero

Research output: Contribution to journalArticle

73 Scopus citations

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 non-epigenetic 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.

Original languageEnglish (US)
Pages (from-to)2732-2741
Number of pages10
JournalBlood
Volume116
Issue number15
DOIs
StatePublished - Oct 14 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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