Abstract
Darinaparsin (Dar) is a more potent cytotoxic arsenical than arsenic trioxide (ATO). We hypothesized that the increased cytotoxicity of Dar may be because of a decreased cytoprotective response. We observed that, unlike ATO, Dar does not induce heme oxygenase-1 (HO-1), even though it induces expression of other nuclear factor (erythroid-derived 2)-like 2 (NRF2)-dependent detoxifying enzymes to a greater extent than ATO, in both cancer cell lines and patient-derived leukemic cells. This strengthens the emerging evidence, showing that response to reactive oxygen species (ROS) is stimuli specific. Dar treatment prevents recruitment of the transcriptional coregulator Brahma-related gene 1 (BRG1) to the HMOX1 promoter, which is required for HMOX1 expression. The inability of Dar to induce HO-1 correlates with arrest in G2/M cell cycle phase and BRG1 phosphorylation. Inhibition of HO-1 increases the toxicity of ATO, but has no effect on Dar-induced apoptosis. Accordingly, the lack of HO-1 induction is involved in Dar's enhanced antileukemic properties. Our data highlight cytoprotective responses mediated by HO-1 and BRG1 as a novel target for enhancing the therapeutic range of arsenicals.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Arsenic Trioxide
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Arsenicals / pharmacology*
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Blast Crisis / drug therapy
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Blast Crisis / metabolism
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Blast Crisis / pathology*
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Blotting, Western
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Chromatin Immunoprecipitation
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Cytoprotection / drug effects*
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Flow Cytometry
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Glutathione / analogs & derivatives*
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Glutathione / pharmacology
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism*
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Humans
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Leukemia, Promyelocytic, Acute / drug therapy
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Leukemia, Promyelocytic, Acute / metabolism
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Leukemia, Promyelocytic, Acute / pathology*
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxides / pharmacology
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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Reactive Oxygen Species / metabolism
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
Substances
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Arsenicals
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NF-E2-Related Factor 2
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Nuclear Proteins
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Oxides
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RNA, Messenger
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Reactive Oxygen Species
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Transcription Factors
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darinaparsin
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HMOX1 protein, human
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Heme Oxygenase-1
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SMARCA4 protein, human
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DNA Helicases
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Glutathione
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Arsenic Trioxide