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2016 ; 7
(39
): 62799-62813
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?-Secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the
proteasome among its targets
#MMPMID27588497
Dorneburg C
; Goß AV
; Fischer M
; Roels F
; Barth TF
; Berthold F
; Kappler R
; Oswald F
; Siveke JT
; Molenaar JJ
; Debatin KM
; Beltinger C
Oncotarget
2016[Sep]; 7
(39
): 62799-62813
PMID27588497
show ga
As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities
are needed. We therefore investigated the susceptibility of NB cells to
?-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.
|Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
[MESH]
free
free
free
