| Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. | |
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MedLine Citation:
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PMID: 20679231 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (gammaH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, gammaH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death. |
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Authors:
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J-H Lee; M L Choy; L Ngo; S S Foster; Paul A Marks |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-02 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-18 Completed Date: 2010-09-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 14639-44 Citation Subset: IM |
Affiliation:
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Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation
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drug effects Antineoplastic Agents / pharmacology Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects, genetics Cells, Cultured DNA Breaks, Double-Stranded / drug effects DNA Damage* DNA Repair* Dose-Response Relationship, Drug Fibroblasts / cytology, drug effects, metabolism Flow Cytometry Foreskin / cytology Histone Deacetylase Inhibitors / pharmacology* Histones / metabolism Humans Hydroxamic Acids / pharmacology* Immunoblotting Male Microscopy, Fluorescence |
| Grant Support | |
ID/Acronym/Agency:
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P30CA08748-44/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/H2AFX protein, human; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/Hydroxamic Acids; 149647-78-9/vorinostat |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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