title: γ-Secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets.
abstract: As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to γ-secretase inhibitor I (GSI-I). NOTCH signaling activity, the cellular effects of GSI-I and its mechanisms of cytotoxicity were evaluated in NB cells in vitro and in vivo. The results show that NOTCH signaling is relevant for human NB cells. Of the GSIs screened in vitro GSI-I was the most effective inhibitor of NB cells. Both MYCN-amplified and non-amplified NB cells were susceptible to GSI-I. Among the targets of GSI-I in NB cells were NOTCH and the proteasome. GSI-I caused G2/M arrest that was enhanced by acute activation of MYCN and led to mitotic dysfunction. GSI-I also induced proapoptotic NOXA. Survival of mice bearing an MYCN non-amplified orthotopic patient-derived NB xenograft was significantly prolonged by systemic GSI-I, associated with mitotic catastrophe and reduced angiogenesis, and without evidence of intestinal toxicity. In conclusion, the activity of GSI-I on multiple targets in NB cells and the lack of gastrointestinal toxicity in mice are advantageous and merit further investigations of GSI-I in NB.
authors: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors: Carmen
authors: C
authors: Dorneburg
authors: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors: Annika V
authors: AV
authors: Goß
authors: Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
authors: Matthias
authors: M
authors: Fischer
authors: Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
authors: Frederik
authors: F
authors: Roels
authors: Department of Pathology, University Medical Center Ulm, Ulm, Germany.
authors: Thomas F E
authors: TF
authors: Barth
authors: Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
authors: Frank
authors: F
authors: Berthold
authors: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors: Roland
authors: R
authors: Kappler
authors: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors: Franz
authors: F
authors: Oswald
authors: Department of Internal Medicine, University Hospital Essen, Essen, Germany.
authors: Jens T
authors: JT
authors: Siveke
authors: Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands.
authors: Jan J
authors: JJ
authors: Molenaar
authors: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors: Christian
authors: C
authors: Beltinger
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008938:Mitosis; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; C459801:MYCN protein, human; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; C497761:NOTCH1 protein, human; D009842:Oligopeptides; D051881:Receptor, Notch1; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex
keywords: NOTCH; in vivo; neuroblastoma; preclinical; γ-secretase inhibitor