| Formaldehyde-releasing prodrugs specifically affect cancer cells by depletion of intracellular glutathione and augmentation of reactive oxygen species. | |
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MedLine Citation:
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PMID: 18030472 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Histone deacetylase inhibitory prodrugs that are metabolized to carboxylic acid(s) and aldehyde(s) possess antineoplastic properties. Formaldehyde-releasing prodrugs were shown to be the most potent. The objective of this study was to gain understanding on the mode of action of these prodrugs in cancer cells. HL-60 and MCF-7 cells in the presence of N-acetylcysteine or glutathione were protected from death induced by formaldehyde-releasing prodrugs but not from death caused by the homologous acetaldehyde-releasing ones. Cell death induced by the former was accompanied by depletion of intracellular glutathione and increased reactive oxygen species that were attenuated by N-acetylcysteine. At fourfold higher concentration, acetaldehyde-releasing prodrugs increased reactive oxygen species that were further augmented by N-acetylcysteine. In HL-60 cells, formaldehyde-releasing prodrugs dissipated the mitochondrial membrane potential and glutathione or N-acetylcysteine restored it. Although acetaldehyde-releasing prodrugs dissipated mitochondrial membrane potential, it occurred at 20-fold greater concentration and was unaffected by the antioxidants. Formaldehyde-releasing prodrugs abrogated c-myc protein expression and elevated c-Jun and H2AX phosphorylation, N-acetylcysteine partially reversed these changes. Herein, we show that formaldehyde-releasing prodrugs diminish the level of glutathione most likely by forming S-formylglutathione adducts resulting in increase of reactive oxygen species followed by signaling events that lead to cancer cells death. |
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Authors:
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Inesa Levovich; Abraham Nudelman; Gili Berkovitch; Lonnie P Swift; Suzanne M Cutts; Don R Phillips; Ada Rephaeli |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-11-21 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 62 ISSN: 0344-5704 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-06-18 Completed Date: 2008-09-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 471-82 Citation Subset: IM |
Affiliation:
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Chemistry Department, Bar Ilan University, Ramat Gan, Israel. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetaldehyde
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chemistry,
pharmacology Acetylcysteine / pharmacology Antineoplastic Agents / chemistry, pharmacology* Apoptosis / drug effects* Blotting, Western Cell Line, Tumor Formaldehyde / chemistry, pharmacology* Glutathione / metabolism* Humans Membrane Potential, Mitochondrial / drug effects Molecular Structure Prodrugs / chemistry, pharmacology* Reactive Oxygen Species / metabolism* Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Prodrugs; 0/Reactive Oxygen Species; 50-00-0/Formaldehyde; 616-91-1/Acetylcysteine; 70-18-8/Glutathione; 75-07-0/Acetaldehyde |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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