Document Detail

Apoptosis of N-type neuroblastoma cells after differentiation with 9-cis-retinoic acid and subsequent washout.
MedLine Citation:
PMID:  9091647     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The overall survival rate for patients with neuroblastoma has improved over the past two decades, but long-term survival for the subgroup of patients with high-risk disease remains low. In recent years, there has been interest in the potential clinical use of drugs able to induce differentiation of neuroblastoma cells. Since 9-cis-retinoic acid induces better and more sustained differentiation of neuroblastoma in vitro than other retinoic acid isomers, this may be a more appropriate retinoid for use in neuroblastoma therapy. PURPOSE: The purpose of this work was to compare the long-term effects of all-trans- and 9-cis-retinoic acid on neuroblastoma differentiation using an N-type (neuroblastic) cell line, SH SY 5Y, as an in vitro model. In addition, we wanted to find out whether 9-cis-retinoic acid would induce programmed cell death (apoptosis) in these N-type neuroblastoma cells and to determine whether the effects of either 9-cis- or all-trans-retinoic acid are dependent on their continued presence in the culture medium. METHODS: SH SY 5Y cells were incubated in either the continued presence of all-trans- or 9-cis-retinoic acid or for 5 days with retinoic acid followed by culture in the absence of retinoid for up to 13 days. Morphologic changes were observed using phase-contrast and scanning electron microscopy. Apoptosis was determined by flow cytometry of propidium iodide-stained cells and by using terminal deoxynucleotidyl transferase to end-label DNA fragments in situ in apoptotic cells. RESULTS: Culture of SH SY 5Y cells with all-trans- or 9-cis retinoic acid for 5 days induced morphologic differentiation and inhibited cell growth. These effects were maintained in the continuous presence of each retinoic acid isomer but were more profound in cells treated with 9-cis-retinoic acid. The differentiation of cells treated with all-trans-retinoic acid was reversible once retinoic acid was removed from the medium. Conversely, apoptosis was induced in cells treated with 9-cis-retinoic acid for 5 days and cultured for 9 days (4 days after washout) but not in cells cultured in the continuous presence of 9-cis-retinoic acid. This effect was specific to 9-cis-retinoic acid. CONCLUSIONS: Previous studies have demonstrated differential responses to all-trans-retinoic acid in N- and S-type (substrate-adherent or Schwann-like) neuroblastoma cells: Apoptosis is induced in S-type cells, whereas differentiation occurs in N-type cells. The present results show that, unlike all-trans-retinoic acid, 9-cis-retinoic acid induces both differentiation and apoptosis in N-type SH SY 5Y neuroblastoma cells. However, apoptosis was dependent on removal of 9-cis-retinoic acid from the culture medium. IMPLICATIONS: Since both differentiation and apoptosis are involved in tumor regression, 9-cis-retinoic acid may be a more appropriate retinoid for clinical trials in neuroblastoma. The dependence of apoptosis on treatment and subsequent removal of 9-cis-retinoic acid implies that drug scheduling may be an important parameter affecting therapeutic efficacy.
P E Lovat; H Irving; M Annicchiarico-Petruzzelli; F Bernassola; A J Malcolm; A D Pearson; G Melino; C P Redfern
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the National Cancer Institute     Volume:  89     ISSN:  0027-8874     ISO Abbreviation:  J. Natl. Cancer Inst.     Publication Date:  1997 Mar 
Date Detail:
Created Date:  1997-04-08     Completed Date:  1997-04-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7503089     Medline TA:  J Natl Cancer Inst     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  446-52     Citation Subset:  IM    
Department of Medicine, University of Newcastle Upon Tyne, U.K.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
DNA Nucleotidylexotransferase
Flow Cytometry
Immunoenzyme Techniques
Neuroblastoma / classification,  drug therapy*,  pathology,  physiopathology*
Time Factors
Tretinoin / pharmacology*
Tumor Cells, Cultured
Reg. No./Substance:
0/Antineoplastic Agents; 302-79-4/Tretinoin; 5300-03-8/alitretinoin; EC Nucleotidylexotransferase

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

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