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Histone deacetylase inhibitor-mediated radiosensitization of human cancer cells: class differences and the potential influence of p53

Cited 60 time in Web of Science Cited 64 time in Scopus
Authors
Kim, In Ah; Shin, Jin Hee; Kim, Il Han; Kim, Jin Ho; Kim, Jae Sung; Wu, Hong Gyun; Chie, Eui Kyu; Ha, Sung Whan; Park, Charn Il; Kao, Gary D
Issue Date
2006-02-10
Publisher
American Association for Cancer Research
Citation
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):940-9.
Keywords
Amides/pharmacologyBenzothiazolesBiphenyl Compounds/pharmacologyCell Cycle/drug effects/radiation effectsCell Line, TumorCell Proliferation/drug effects/radiation effectsDose-Response Relationship, DrugDose-Response Relationship, RadiationEnzyme Inhibitors/*pharmacologyFatty Acids, Unsaturated/pharmacologyGene Expression Regulation/drug effectsHela CellsHistone Deacetylases/*antagonists & inhibitors/*classification/radiationeffectsHumansHydroxamic Acids/antagonists & inhibitors/pharmacologyNaphthalenes/pharmacologyPyrones/pharmacologyRadiation-Sensitizing Agents/*pharmacologyThiazoles/pharmacologyToluene/analogs & derivatives/pharmacologyTumor Cells, CulturedTumor Suppressor Protein p53/*drug effects/genetics/radiation effects
Abstract
Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-alpha, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53-expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.
ISSN
1078-0432 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16467109

http://hdl.handle.net/10371/29034
DOI
https://doi.org/10.1158/1078-0432.CCR-05-1230
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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