Document Detail


Hydroxyurea-induced apoptosis in an EBV-immortalized lymphoblastoid cell line.
MedLine Citation:
PMID:  14977355     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hydroxyurea (HU) is an inhibitor of nucleotide synthesis extensively used to control the chronic phase of myeloid leukemia. This antimetabolite has been employed in the clinic for several decades but in recent years the leukemogenic potential of HU has been suspected. In the present study, a B-lymphoblastoid cell line transformed by the Epstein-Barr virus was used to investigate the apoptotic effects of HU and delineate some of the molecular pathways implicated in the cytotoxic action. The cell line, characterized by immunophenotyping, cytogenetic and fluorescence in situ hybridization (FISH) studies, showed no chromosomal abnormalities, even after a prolonged exposure to HU. Different flow cytometry assays were used to measure HU-induced impairment of the cell cycle, inhibition of DNA synthesis, and the occurrence of apoptosis. The treatment with HU leads to the appearance of a hypo-diploid DNA content peak (sub-G1) characteristic of the apoptotic cell population. The drug also induces a cell block in S phase as measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation. Inhibition of DNA synthesis precedes induction of apoptosis by HU. A drug-induced loss of plasma membrane asymmetry was characterized by flow cytometry using annexin V-FITC to stain phosphatidylserine residues. The implication of the antiapoptotic protein Bcl-2 and the tumor suppressor p53 in the development of HU-mediated apoptosis was also evidenced. The drug appears to promote cell death by regulating the expression levels of these two proteins. Different criteria define the apoptotic response of the lymphoblastoid cells to the treatment with HU. However, the extent of drug-induced cell death is limited, and no DNA fragmentation and no activation of the caspase cascade was observed in this model. Beyond the specific interest in HU-induced apoptosis, the work reported here illustrates the utility of the EBV immortalization process to investigate the pharmacological activity of specific drugs from clinical samples.
Authors:
Pauline Huyghe; Laurent Dassonneville; Pierre Fenaux; Christian Bailly
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncology research     Volume:  14     ISSN:  0965-0407     ISO Abbreviation:  Oncol. Res.     Publication Date:  2004  
Date Detail:
Created Date:  2004-02-23     Completed Date:  2004-09-03     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9208097     Medline TA:  Oncol Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  235-45     Citation Subset:  IM    
Affiliation:
INSERM U-524, Institut de Recherches sur le Cancer de Lille, 1 Place de Verdun, 59045 Lille cedex, France.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Bromodeoxyuridine / metabolism
Cell Cycle / drug effects
Cell Line, Transformed
Cell Membrane / metabolism
Flow Cytometry
Herpesvirus 4, Human / physiology*
Humans
Hydroxyurea / pharmacology*
Immunophenotyping
In Situ Hybridization, Fluorescence
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism,  pathology*,  virology*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Protein p53; 127-07-1/Hydroxyurea; 59-14-3/Bromodeoxyuridine

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


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