Oncotarget

Priority Research Papers:

γ-secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets

Carmen Dorneburg, Annika V. Goß, Matthias Fischer, Frederik Roels, Thomas F.E. Barth, Frank Berthold, Roland Kappler, Franz Oswald, Jens T. Siveke, Jan J. Molenaar, Klaus-Michael Debatin and Christian Beltinger _

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Oncotarget. 2016; 7:62799-62813. https://doi.org/10.18632/oncotarget.11715

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Abstract

Carmen Dorneburg1, Annika V. Goß1, Matthias Fischer2, Frederik Roels2, Thomas F.E. Barth3, Frank Berthold2, Roland Kappler4, Franz Oswald5, Jens T. Siveke6, Jan J. Molenaar7, Klaus-Michael Debatin1, and Christian Beltinger1

1 Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany

2 Children’s Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany

3 Department of Pathology, University Medical Center Ulm, Ulm, Germany

4 Department of Pediatric Surgery, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany

5 Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany

6 Department of Internal Medicine, University Hospital Essen, Essen, Germany

7 Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands

Correspondence to:

Christian Beltinger, email:

Keywords: γ-secretase inhibitor, NOTCH, neuroblastoma, preclinical, in vivo

Received: March 04, 2016 Accepted: August 12, 2016 Published: August 30, 2016

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.


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