Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma
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Tiago Elias Heinen1,2, Rafael Pereira dos Santos1,2, Amanda da Rocha1,2, Michel Pinheiro dos Santos3, Patrícia Luciana da Costa Lopez1,2, Marco Aurélio Silva Filho1,2, Bárbara Kunzler Souza1,2, Luís Fernando da Rosa Rivero4, Ricardo Gehrke Becker5, Lauro José Gregianin1,6,8, Algemir Lunardi Brunetto7, André Tesainer Brunetto7, Caroline Brunetto de Farias1,7, Rafael Roesler1,2
1Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
2Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
3Faculty of Health Sciences, UniRitter Laureate International Universities, Porto Alegre, RS, Brazil
4Departament of Pathology, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
5Department of Orhopaedics and Traumatology, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
6Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
7Children’s Cancer Institute (ICI), Porto Alegre, RS, Brazil
8Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
Rafael Roesler, e-mail: [email protected]
Keywords: TrkA, TrkB, neurotrophin, neurotrophin receptor, Ewing sarcoma
Received: October 05, 2015 Accepted: April 10, 2016 Published: April 26, 2016
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.
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