Abstract
Dithiolethiones upregulate the expression of cancer-preventive proteins via modification of thiol residues in the Keap1-Nrf2 transcription factor complex. In addition to Keap1-Nrf2, dithiolethiones have the potential to modify a variety of cysteine-containing proteins in the cell. Such 'off target' reactions could contribute to either side effects or cancer-preventive efficacy. Evidence is presented here that cancer chemopreventive dithiolethiones inactivate protein tyrosine phosphatases via covalent, but thiol-labile, modification of active site residues. This observation may explain a number of previously reported cellular responses to dithiolethiones.
Copyright 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Anticarcinogenic Agents / pharmacology*
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Catalytic Domain / drug effects
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Humans
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Mass Spectrometry
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / chemistry
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Protein Tyrosine Phosphatases / metabolism*
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Pyrazines / pharmacology*
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Reactive Oxygen Species / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Thiones / pharmacology*
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Thiophenes / pharmacology*
Substances
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Anticarcinogenic Agents
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Pyrazines
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Reactive Oxygen Species
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Recombinant Proteins
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Thiones
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Thiophenes
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oltipraz
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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1,2-dithiol-3-thione