Format

Send to

Choose Destination
Oncotarget. 2016 Jun 7;7(23):34860-80. doi: 10.18632/oncotarget.8992.

Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma.

Author information

1
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
2
Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
3
Faculty of Health Sciences, UniRitter Laureate International Universities, Porto Alegre, RS, Brazil.
4
Departament of Pathology, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
5
Department of Orhopaedics and Traumatology, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
6
Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
7
Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
8
Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.

Abstract

Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES.

KEYWORDS:

Ewing sarcoma; TrkA; TrkB; neurotrophin; neurotrophin receptor

PMID:
27145455
PMCID:
PMC5085195
DOI:
10.18632/oncotarget.8992
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflicts of interest.

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center