RESUMEN

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 ß-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.

Asunto(s)

Antineoplásicos/farmacología , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Glicoproteínas de Membrana/antagonistas & inhibidores , Factor de Crecimiento Nervioso/biosíntesis , Receptor trkA/antagonistas & inhibidores , Receptor trkB/antagonistas & inhibidores , Sarcoma de Ewing/tratamiento farmacológico , Azepinas/farmacología , Benzamidas/farmacología , Factor Neurotrófico Derivado del Encéfalo/genética , Carbazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Inhibidores Enzimáticos/farmacología , Etopósido/farmacología , Humanos , Alcaloides Indólicos/farmacología , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Factor de Crecimiento Nervioso/genética , ARN Mensajero/biosíntesis , Receptor trkA/biosíntesis , Receptor trkA/genética , Receptor trkB/biosíntesis , Receptor trkB/genética , Sarcoma de Ewing/patología , Tubulina (Proteína)/metabolismo , Vincristina/farmacología