Document Detail

Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells.
MedLine Citation:
PMID:  20716592     Owner:  NLM     Status:  MEDLINE    
High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking γ-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13-cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neuronal differentiation, and significantly reduced cell motility. The combination of GSIs and 13-cis RA resulted in the enhanced growth inhibition, differentiation, and migration of neuroblastoma cells. In summary, our data suggest that a combination of GSIs with 13-cis RA offers a therapeutic advantage over a single agent, indicating a potential novel therapy for neuroblastoma.
Giulia Ferrari-Toninelli; Sara Anna Bonini; Daniela Uberti; Laura Buizza; Paola Bettinsoli; Pietro Luigi Poliani; Fabio Facchetti; Maurizio Memo
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-17
Journal Detail:
Title:  Neuro-oncology     Volume:  12     ISSN:  1523-5866     ISO Abbreviation:  Neuro-oncology     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-18     Completed Date:  2011-03-18     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1231-43     Citation Subset:  IM    
Department of Biomedical Sciences and Biotechnologies, University of Brescia Medical School, Brescia, Italy.
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MeSH Terms
Amyloid Precursor Protein Secretases / antagonists & inhibitors*,  metabolism
Apoptosis / drug effects
Benzodiazepinones / pharmacology
Blotting, Western
Calcium-Binding Proteins / metabolism
Cell Cycle / drug effects
Cell Differentiation / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Dermatologic Agents / pharmacology
Drug Therapy, Combination
Flow Cytometry
Intercellular Signaling Peptides and Proteins / metabolism
Isotretinoin / pharmacology
Membrane Proteins / metabolism
Neuroblastoma / drug therapy,  metabolism,  pathology*
Oligopeptides / pharmacology
Peptide Fragments / pharmacology
RNA, Messenger / genetics
Receptors, Notch / antagonists & inhibitors*,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Wound Healing / drug effects*
Reg. No./Substance:
0/2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; 0/2-(2-(3,5-difluorophenyl)-acetylamino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)propionamide; 0/Benzodiazepinones; 0/Calcium-Binding Proteins; 0/Dermatologic Agents; 0/Intercellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Oligopeptides; 0/Peptide Fragments; 0/RNA, Messenger; 0/Receptors, Notch; 0/benzyloxycarbonyl-leucyl-leucyl-norleucinal; 134324-36-0/Serrate proteins; 4759-48-2/Isotretinoin; EC 3.4.-/Amyloid Precursor Protein Secretases

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