TY - JOUR
T1 - The novel kinase inhibitor EMD1214063 is effective against neuroblastoma
AU - Scorsone, Kathy
AU - Zhang, Linna
AU - Woodfield, Sarah E.
AU - Hicks, John
AU - Zage, Peter
N1 - Publisher Copyright:
© Springer Science+Business Media New York 2014.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2014/10
Y1 - 2014/10
N2 - Background: Children with high-risk neuroblastoma have poor survival rates, and novel therapies are needed. Previous studies have identified a role for the HGF/c-Met pathway in neuroblastoma pathogenesis. We hypothesized that EMD1214063 would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of HGF/c-Met signaling. Methods: We determined the expression of c-Met protein by Western blots in a panel of neuroblastoma tumor cell lines and neuroblastoma cell viability after treatment with EMD1214063 using MTT assays. TUNEL assays and assays for DNA ladder formation, were performed to measure the induction of apoptosis after EMD1214063 treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. To investigate the efficacy of EMD1214063 against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and mice were treated with oral EMD1214063. Tumors were evaluated for growth, histologic appearance, and induction of apoptosis by immunohistochemistry. Results: All neuroblastoma cell lines were sensitive to EMD1214063, and IC50 values ranged from 2.4 to 8.5 μM. EMD1214063 treatment inhibited HGF-mediated c-Met phosphorylation and MEK phosphorylation in neuroblastoma cells. EMD1214063 induced apoptosis in all tested cell lines. Inmice with neuroblastoma xenograft tumors, EMD1214063 treatment reduced tumor growth. Conclusions: Treatment of neuroblastoma tumor cells with EMD1214063 inhibits HGF-induced c-Met phosphorylation and results in cell death. EMD1214063 treatment is also effective in reducing tumor growth in vivo. EMD1214063 therefore represents a novel therapeutic agent for neuroblastoma, and further preclinical studies of EMD1214063 are warranted.
AB - Background: Children with high-risk neuroblastoma have poor survival rates, and novel therapies are needed. Previous studies have identified a role for the HGF/c-Met pathway in neuroblastoma pathogenesis. We hypothesized that EMD1214063 would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of HGF/c-Met signaling. Methods: We determined the expression of c-Met protein by Western blots in a panel of neuroblastoma tumor cell lines and neuroblastoma cell viability after treatment with EMD1214063 using MTT assays. TUNEL assays and assays for DNA ladder formation, were performed to measure the induction of apoptosis after EMD1214063 treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. To investigate the efficacy of EMD1214063 against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and mice were treated with oral EMD1214063. Tumors were evaluated for growth, histologic appearance, and induction of apoptosis by immunohistochemistry. Results: All neuroblastoma cell lines were sensitive to EMD1214063, and IC50 values ranged from 2.4 to 8.5 μM. EMD1214063 treatment inhibited HGF-mediated c-Met phosphorylation and MEK phosphorylation in neuroblastoma cells. EMD1214063 induced apoptosis in all tested cell lines. Inmice with neuroblastoma xenograft tumors, EMD1214063 treatment reduced tumor growth. Conclusions: Treatment of neuroblastoma tumor cells with EMD1214063 inhibits HGF-induced c-Met phosphorylation and results in cell death. EMD1214063 treatment is also effective in reducing tumor growth in vivo. EMD1214063 therefore represents a novel therapeutic agent for neuroblastoma, and further preclinical studies of EMD1214063 are warranted.
KW - C-Met
KW - EMD1214063
KW - MEK
KW - Neuroblastoma
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UR - http://www.scopus.com/inward/citedby.url?scp=84930736403&partnerID=8YFLogxK
U2 - 10.1007/s10637-014-0107-4
DO - 10.1007/s10637-014-0107-4
M3 - Article
C2 - 24832869
AN - SCOPUS:84930736403
SN - 0167-6997
VL - 32
SP - 815
EP - 824
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 5
ER -