PMID- 25700942
OWN - NLM
STAT- MEDLINE
DCOM- 20160101
LR  - 20200930
IS  - 1555-8576 (Electronic)
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 16
IP  - 3
DP  - 2015
TI  - Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells 
      from etoposide in vitro and in vivo.
PG  - 477-83
LID - 10.1080/15384047.2015.1016659 [doi]
AB  - TrkB activation by brain-derived neurotrophic factor (BDNF) contributes to 
      chemo-resistance in neuroblastoma (NB). AZD6918 is a novel potent and selective 
      inhibitor of the Trk tyrosine kinases. In this study we evaluated the effect of 
      AZD6918 on the sensitivity of TrkB-expressing NB cells or tumors to etoposide, a 
      topoisomerase II inhibitor. TrkB-expressing NB cells were treated with AZD6918 
      and etoposide in the presence or absence of BDNF in vitro and cell survival was 
      determined. NB xenograft tumors were treated with AZD6918 and etoposide, either 
      alone or in combination in vivo, and the anti-tumor growth effect or mice 
      survival advantage was evaluated. Our study showed that AZD6918 induced cell 
      death as a single agent and attenuated BDNF/TrkB-induced protection from 
      etoposide in vitro. Although AZD6918 alone didn't show anti-tumor growth effect 
      or survival advantage in vivo, a combination of AZD6918 and etoposide had a 
      statistically significant stronger anti-tumor growth effect and survival 
      advantage compared to treatment with either agent alone. Our data indicate that 
      as a Trk inhibitor AZD6918 increased the sensitivity of NB to etoposide. These 
      results extend the spectrum of cytotoxic drugs whose efficacy is increased in 
      combination with Trk inhibitors and support the combination of Trk inhibitors and 
      cytotoxic drugs for NB treatment.
FAU - Li, Zhijie
AU  - Li Z
AD  - a Cell & Molecular Biology Section, Pediatric Oncology Branch , National 
      Institutes of Health , Bethesda , MD , USA.
FAU - Zhang, Yi
AU  - Zhang Y
FAU - Tong, Yuxin
AU  - Tong Y
FAU - Tong, Jenna
AU  - Tong J
FAU - Thiele, Carol J
AU  - Thiele CJ
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.10.1 (tropomyosin-related kinase-B, human)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Brain-Derived Neurotrophic Factor/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Drug Resistance, Neoplasm/drug effects/genetics
MH  - Etoposide/administration & dosage
MH  - Humans
MH  - Membrane Glycoproteins/*biosynthesis/genetics
MH  - Mice
MH  - Neuroblastoma/*drug therapy/genetics/pathology
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/*administration & dosage
MH  - Protein-Tyrosine Kinases/*biosynthesis/genetics
MH  - Receptor, trkB
PMC - PMC4623105
OTO - NOTNLM
OT  - AZD6918
OT  - BDNF, brain-derived neurotrophic factor
OT  - NB, neuroblastoma
OT  - TET, tetracycline
OT  - Trk inhibitor
OT  - Trk, tropomyosin-related kinase
OT  - etoposide
OT  - neuroblastoma
EDAT- 2015/02/24 06:00
MHDA- 2016/01/02 06:00
PMCR- 2016/02/20
CRDT- 2015/02/22 06:00
PHST- 2015/02/22 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2016/01/02 06:00 [medline]
PHST- 2016/02/20 00:00 [pmc-release]
AID - 1016659 [pii]
AID - 10.1080/15384047.2015.1016659 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2015;16(3):477-83. doi: 10.1080/15384047.2015.1016659.