Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Apoptosis / drug effects
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Benzodiazepinones / pharmacology
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Blotting, Western
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Calcium-Binding Proteins / metabolism
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Cell Cycle / drug effects
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Cell Differentiation / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dermatologic Agents / pharmacology
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Drug Therapy, Combination
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Flow Cytometry
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Isotretinoin / pharmacology
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Jagged-1 Protein
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Membrane Proteins / metabolism
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Neuroblastoma / drug therapy
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Neuroblastoma / metabolism
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Neuroblastoma / pathology*
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Oligopeptides / pharmacology
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Peptide Fragments / pharmacology
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RNA, Messenger / genetics
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Receptors, Notch / antagonists & inhibitors*
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Receptors, Notch / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Signal Transduction
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Wound Healing / drug effects*
Substances
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2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
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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
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Benzodiazepinones
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Calcium-Binding Proteins
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Dermatologic Agents
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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Oligopeptides
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Peptide Fragments
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RNA, Messenger
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Receptors, Notch
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Serrate-Jagged Proteins
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benzyloxycarbonyl-leucyl-leucyl-norleucinal
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Amyloid Precursor Protein Secretases
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Isotretinoin