Document Detail

DNA damage responses triggered by a highly cytotoxic monofunctional DNA alkylator, hedamycin, a pluramycin antitumor antibiotic.
MedLine Citation:
PMID:  15141015     Owner:  NLM     Status:  MEDLINE    
Long-term exposure (72 h) to hedamycin, a monofunctional DNA alkylator of the pluramycin class of antitumor antibiotics, decreased growth of mammalian cells by 50% at subnanomolar concentrations. Short-term treatment (4 h) rapidly reduced DNA synthesis by 50% also at subnanomolar concentrations, but substantially higher levels were needed to block RNA synthesis while protein synthesis even at very high hedamycin concentrations remained unaffected. Hedamycin treatment at concentrations below its growth IC(50) induced only a transient and temporary accumulation of cells in G(2). Somewhat higher concentrations resulted in substantial S-phase arrest, and at increasing concentrations, complete cell cycle arrest in G(1) was observed without the appearance of a sub-G(1) cell population. Neither inhibition of cell growth nor cell cycle arrest appeared to be dependent on ataxia and Rad-related kinase expression. DNA damage checkpoint proteins including p53, chk1, and chk2 were differentially activated by hedamycin depending on the concentration and duration of treatment. The level of downstream cell cycle regulators such as cdc25A, E2F1, cyclin E, and p21 were also altered under conditions that induced cell cycle arrest, but atypically, p21 overexpression was observed only in S-phase-arrested cells. Apoptotic indicators were only observed at moderate hedamycin concentrations associated with S-phase arrest, while increasing concentrations, when cells were arrested in G(1), resulted in a reduction of these signals. Taken together, the responses of cells to hedamycin are distinct with regard to its effect on cell cycle but also in the unusual concentration-dependent manner of activation of DNA damage and cell cycle checkpoint proteins as well as the induction of apoptotic-associated events.
Lan Chun Tu; Thomas Melendy; Terry A Beerman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  3     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-05-13     Completed Date:  2005-01-11     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  577-85     Citation Subset:  IM    
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
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MeSH Terms
Alkylating Agents / pharmacology*
Aminoglycosides / pharmacology*
Anthraquinones / pharmacology*
Antibiotics, Antineoplastic / pharmacology*
Cell Cycle / drug effects
Cell Cycle Proteins / metabolism
Cell Division / drug effects
Cyclin E / metabolism
Cytotoxins / pharmacology*
DNA / biosynthesis
DNA Damage / drug effects*
DNA Nucleotidylexotransferase / metabolism
DNA-Binding Proteins / metabolism
E2F Transcription Factors
E2F1 Transcription Factor
HCT116 Cells
Inhibitory Concentration 50
Poly(ADP-ribose) Polymerases / metabolism
Protein Biosynthesis / drug effects
RNA / biosynthesis
S Phase / drug effects
Transcription Factors / metabolism
cdc25 Phosphatases / metabolism
Grant Support
Reg. No./Substance:
0/Alkylating Agents; 0/Aminoglycosides; 0/Anthraquinones; 0/Antibiotics, Antineoplastic; 0/Cell Cycle Proteins; 0/Cyclin E; 0/Cytotoxins; 0/DNA-Binding Proteins; 0/E2F Transcription Factors; 0/E2F1 Transcription Factor; 0/E2F1 protein, human; 0/Transcription Factors; 11016-27-6/pluramycin; 11048-97-8/hedamycin; 63231-63-0/RNA; 9007-49-2/DNA; EC Polymerases; EC Nucleotidylexotransferase; EC protein, human; EC Phosphatases

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