Document Detail

Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo- and radiosensitization.
MedLine Citation:
PMID:  19652528     Owner:  NLM     Status:  MEDLINE    
Acetyl group turnover on specific lysine epsilon-amino groups of the core chromosomal histones regulates DNA accessibility function, and the acetylating and deacetylating enzymes that govern the turnover provide important targets for the development of anti-cancer drugs. Histone deacetylase (HDAC) inhibitors have been developed and evaluated extensively in clinical trials, while the development of inhibitors of histone acetyltransferase (HAT) has proceeded more slowly. Here we have examined the cellular effects of an S-substituted coenzyme A (CoA) inhibitor of histone acetylation, consisting of spermidine (Spd) linked to the S-terminus of CoA through a thioglycolic acid linkage (adduct abbreviated as Spd-CoA), as well as the effects of a truncated Spd-CoA derivative lacking the negatively charged portion of the CoA moiety. While exposure of cancer cells to Spd-CoA has little effect on cell viability, it causes a rapid inhibition of histone acetylation that correlates with a transient arrest of DNA synthesis, a transient delay in S-phase progression, and an inhibition of nucleotide excision repair and DNA double strand break repair. These effects correlate with increased cellular sensitivity to the DNA-targeted chemotherapeutic drugs, cisplatin (Platinol()) and 5-fluorouracil, to the DNA damaging drug, camptothecin, and to UV-C irradiation. The sensitization effects of Spd-CoA are not observed in normal cells due to a barrier to uptake. The truncated Spd-CoA derivative displays similar but enhanced chemosensitization effects, suggesting that further modifications of the Spd-CoA structure could further improve potency. The results demonstrate that Spd-CoA and its truncated version are efficiently and selectively internalized into cancer cells, and suggest that the resulting inhibition of acetylation-dependent DNA repair enhances cellular sensitivity to DNA damage. These and related inhibitors of histone acetylation could therefore constitute a novel class of potent therapy sensitizers applicable to a broad range of conventional cancer treatments.
Keya Bandyopadhyay; Jean-Louis Banères; Aimée Martin; Casimir Blonski; Joseph Parello; Ruth A Gjerset
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-09-02
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  8     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-08     Completed Date:  2009-12-14     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2779-88     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents / chemistry,  pharmacology*
Cell Line, Tumor
Coenzyme A / chemistry,  pharmacology*
DNA Repair*
Histone Acetyltransferases / antagonists & inhibitors*,  metabolism
Histones / metabolism*
Lung Neoplasms / drug therapy
S Phase
Spermidine / analogs & derivatives*,  chemistry,  pharmacology*
Grant Support
R01 CA111868/CA/NCI NIH HHS; R01 CA111868-01/CA/NCI NIH HHS; R01 CA111868-02/CA/NCI NIH HHS; R01 CA111868-03/CA/NCI NIH HHS; R01 CA111868-04/CA/NCI NIH HHS; R01 CA111868-05/CA/NCI NIH HHS; R01 CA111868-06/CA/NCI NIH HHS; R01 CA135369/CA/NCI NIH HHS; R01 CA135369-01/CA/NCI NIH HHS; R01CA111868/CA/NCI NIH HHS; R01CA135369/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/H2AFX protein, human; 0/Histones; EC Acetyltransferases; SAA04E81UX/Coenzyme A; U87FK77H25/Spermidine
Comment In:
Cell Cycle. 2009 Sep 15;8(18):2867   [PMID:  19736512 ]
Erratum In:
Cell Cycle. 2010 Mar;9(5):1023
Note: Dosage error in article text

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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