Document Detail

Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea.
MedLine Citation:
PMID:  17106870     Owner:  NLM     Status:  MEDLINE    
Recently, it was shown that MYCN amplified cells spontaneously expulse extrachromosomally amplified gene copies by micronuclei formation. Furthermore, it was shown that these cells lose their malignant phenotype and start to age. We tested whether it is possible to encourage neuroblastoma tumor cells to enter the senescence pathway by low concentrations of the micronuclei-inducing drug hydroxyurea (HU). We studied the effect of HU on 12 neuroblastoma cell lines with extra- or intrachromosomally amplified MYCN copies and without amplification. Two extrachromosomally amplified neuroblastoma cell lines (with double minutes) were investigated in detail. Already after 3 weeks of HU treatment, the BrdU uptake dropped to 25% of the starting cells. After 4 weeks, enlarged and flattened cells (F-cells) and increased granularity in the majority of cells were observed. A drastic reduction of the MYCN copy number-down to one copy per cell-associated with CD44 and MHCI upregulation in up to 100% of the HU treated neuroblastoma cells was found after 5-8 weeks. Telomere length was reduced to half the length within 8 weeks of HU treatment, and telomerase activity was not detectable at this time, while being strongly expressed at the beginning. All these features and the expression of senescence-associated-beta-galactosidase (SA-beta-GAL) in up to 100% of the cells support the hypothesis that these cells entered the senescence pathway. Thus, low-dose HU is a potent senescence elicitor for tumor cells with gene amplification, possibly representing an attractive additional strategy for treatment of this subset of tumors.
R Narath; I M Ambros; A Kowalska; E Bozsaky; P Boukamp; P F Ambros
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes, chromosomes & cancer     Volume:  46     ISSN:  1045-2257     ISO Abbreviation:  Genes Chromosomes Cancer     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2006-12-07     Completed Date:  2007-10-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9007329     Medline TA:  Genes Chromosomes Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  130-42     Citation Subset:  IM    
Copyright Information:
Copyright 2006 Wiley-Liss, Inc.
Children's Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung, Vienna, Austria.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Cell Aging / drug effects*,  genetics
Cell Line, Tumor
Gene Amplification / physiology*
Hydroxyurea / pharmacology*
Neuroblastoma / drug therapy,  genetics*,  metabolism
Nuclear Proteins / biosynthesis,  genetics*
Oncogene Proteins / biosynthesis,  genetics*
Reg. No./Substance:
0/Antineoplastic Agents; 0/MYCN protein, human; 0/Nuclear Proteins; 0/Oncogene Proteins; 127-07-1/Hydroxyurea

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