Y-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, Christian Beltinger

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

9 Citaten (Scopus)


As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to y-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 MYCNamplified 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.

Originele taal-2Engels
Pagina's (van-tot)62799-62813
Aantal pagina's15
Nummer van het tijdschrift39
StatusGepubliceerd - 27 sep. 2016
Extern gepubliceerdJa


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