Document Detail


Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation.
MedLine Citation:
PMID:  16014567     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Iron is critical for cell growth and proliferation. Iron chelators are being explored for a number of clinical applications, including the treatment of neurodegenerative disorders, heart disease, and cancer. To uncover mechanisms of action of tachpyridine, a chelator currently undergoing preclinical evaluation as an anticancer agent, cell-cycle analysis was performed. Tachpyridine arrested cells at G2, a radiosensitive phase of the cell cycle, and enhanced the sensitivity of cancer cells but not nontransformed cells to ionizing radiation. G2 arrest was p53 independent and was accompanied by activation of the checkpoint kinases CHK1 and CHK2. G2 arrest was blocked by UCN-01, a CHK1 inhibitor, but proceeded in CHK2 knock-out cells, indicating a critical role for CHK1 in G2 arrest. Tachpyridine-induced cell-cycle arrest was abrogated in cells treated with caffeine, an inhibitor of the ataxia-telangiectasia mutated/ataxia-telangiectasia-mutated and Rad3-related (ATM/ATR) kinases. Further, G2 arrest proceeded in ATM-deficient cells but was blocked in ATR-deficient cells, implicating ATR as the proximal kinase in tachpyridine-mediated G2 arrest. Collectively, our results suggest that iron chelators may function as antitumor and radioenhancing agents and uncover a previously unexplored activity of iron chelators in activation of ATR and checkpoint kinases.
Authors:
Jolyn Turner; Constantinos Koumenis; Timothy E Kute; Roy P Planalp; Martin W Brechbiel; Dillon Beardsley; Brooke Cody; Kevin D Brown; Frank M Torti; Suzy V Torti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2005-07-12
Journal Detail:
Title:  Blood     Volume:  106     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2005 Nov 
Date Detail:
Created Date:  2005-10-20     Completed Date:  2005-11-30     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3191-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Biochemistry, Wake Forest University Health Scieces, Winston-Salem, NC 27157, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle Proteins / metabolism
Cell Division / drug effects,  radiation effects
Cell Line, Tumor
Chelating Agents / pharmacology*
Cyclohexylamines / pharmacology*
DNA-Binding Proteins / metabolism
Enzyme Activation / drug effects,  radiation effects
G2 Phase / drug effects*,  radiation effects*
Humans
Metals / antagonists & inhibitors,  metabolism
Neoplasms / metabolism,  pathology
Phosphorylation / drug effects
Protein Kinases / metabolism*
Protein-Serine-Threonine Kinases / metabolism*
Pyridines / pharmacology*
Radiation, Ionizing*
Tumor Suppressor Protein p53 / deficiency,  genetics,  metabolism
Tumor Suppressor Proteins / metabolism
Grant Support
ID/Acronym/Agency:
CA102289/CA/NCI NIH HHS; DK 57781/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Chelating Agents; 0/Cyclohexylamines; 0/DNA-Binding Proteins; 0/Metals; 0/Pyridines; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 0/tachpyr; EC 2.7.-/Protein Kinases; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein
Comments/Corrections

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


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