Document Detail


Molecular basis for G2 arrest induced by 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine and consequences of checkpoint abrogation.
MedLine Citation:
PMID:  16061671     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC) is a nucleoside analogue with a novel mechanism of action that is currently being evaluated in clinical trials. Incorporation of CNDAC triphosphate into DNA and extension during replication leads to single-strand breaks directly caused by beta-elimination. These breaks, or the lesions that arise from further processing, cause cells to arrest in G2. The purpose of this investigation was to define the molecular basis for G2 checkpoint activation and to delineate the sequelae of its abrogation. Cell lines derived from diverse human tissues underwent G2 arrest after CNDAC treatment, suggesting a common mechanism of response to the damage created. CNDAC-induced G2 arrest was instituted by activation of the Chk1-Cdc25C-Cdk1/cyclin B checkpoint pathway. Neither Chk2, p38, nor p53 was required for checkpoint activation. Inhibition of Chk1 kinase with 7-hydroxystaurosporine (UCN-01) abrogated the checkpoint pathway as indicated by dephosphorylation of checkpoint proteins and progression of cells through mitosis and into G1. Cell death was first evident in hematologic cell lines after G1 entry. As indicated by histone H2AX phosphorylation, DNA damage initiated by CNDAC incorporation was transformed into double-strand breaks when ML-1 cells arrested in G2. Some breaks were manifested as chromosomal aberrations when the G2 checkpoint of CNDAC-arrested cells was abrogated by UCN-01 but also in a minor population of cells that escaped to mitosis during treatment with CNDAC alone. These findings provide a mechanistic rationale for the design of new strategies, combining CNDAC with inhibitors of cell cycle checkpoint regulation in the therapy of hematologic malignancies.
Authors:
Xiaojun Liu; Ying Guo; Yexiong Li; Yingjun Jiang; Sherri Chubb; Atsushi Azuma; Peng Huang; Akira Matsuda; Walter Hittelman; William Plunkett
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  65     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-02     Completed Date:  2005-10-04     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6874-81     Citation Subset:  IM    
Affiliation:
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
CDC2 Protein Kinase / metabolism
Cell Line, Tumor
Chromosome Aberrations
Cytarabine / analogs & derivatives*,  antagonists & inhibitors,  pharmacology
DNA Damage
Drug Interactions
G2 Phase / drug effects*,  genetics
Hematologic Neoplasms / drug therapy*,  genetics,  pathology*
Humans
Leukemia, Myeloid, Acute / drug therapy,  genetics,  pathology
Mitosis / drug effects
Protein Kinases / metabolism
Signal Transduction / drug effects
Staurosporine / analogs & derivatives,  pharmacology
Grant Support
ID/Acronym/Agency:
CA28596/CA/NCI NIH HHS; CA55164/CA/NCI NIH HHS; P30 CA16672/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 134665-72-8/2'-cyano-2'-deoxyarabinofuranosylcytosine; 147-94-4/Cytarabine; 62996-74-1/Staurosporine; 7BU5H4V94A/7-hydroxystaurosporine; EC 2.7.-/Protein Kinases; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.22/CDC2 Protein Kinase

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


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