title: Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma.
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.
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Tiago Elias
authors.initials: TE
authors.lastname: Heinen
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Rafael Pereira
authors.initials: RP
authors.lastname: Dos Santos
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Amanda
authors.initials: A
authors.lastname: da Rocha
authors.affiliation: Faculty of Health Sciences, UniRitter Laureate International Universities, Porto Alegre, RS, Brazil.
authors.forename: Michel Pinheiro
authors.initials: MP
authors.lastname: Dos Santos
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Patrícia Luciana da Costa
authors.initials: PL
authors.lastname: Lopez
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: Silva Filho
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Bárbara Kunzler
authors.initials: BK
authors.lastname: Souza
authors.affiliation: Departament of Pathology, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Luís Fernando da Rosa
authors.initials: LF
authors.lastname: Rivero
authors.affiliation: Department of Orhopaedics and Traumatology, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Ricardo Gehrke
authors.initials: RG
authors.lastname: Becker
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Lauro José
authors.initials: LJ
authors.lastname: Gregianin
authors.affiliation: Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.
authors.forename: Algemir Lunardi
authors.initials: AL
authors.lastname: Brunetto
authors.affiliation: Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.
authors.forename: André Tesainer
authors.initials: AT
authors.lastname: Brunetto
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.
authors.forename: Caroline Brunetto
authors.initials: CB
authors.lastname: de Farias
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Rafael
authors.initials: R
authors.lastname: Roesler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020932:Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
chemical_list: C559317:ANA 12 compound; D000970:Antineoplastic Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D008562:Membrane Glycoproteins; C502240:NGF protein, human; C000611485:NTRK1 protein, human; D012333:RNA, Messenger; C498585:TUBB3 protein, human; D014404:Tubulin; D014750:Vincristine; D005047:Etoposide; C579455:BDNF protein, human; D004317:Doxorubicin; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D020917:Receptor, trkA; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: Ewing sarcoma; TrkA; TrkB; neurotrophin; neurotrophin receptor