Heinen Tiago Elias, Dos Santos Rafael Pereira, da Rocha Amanda, Dos Santos Michel Pinheiro, Lopez Patrícia Luciana da Costa, Silva Filho Marco Aurélio, Souza Bárbara Kunzler, Rivero Luís Fernando da Rosa, Becker Ricardo Gehrke, Gregianin Lauro José, Brunetto Algemir Lunardi, Brunetto André Tesainer, de Farias Caroline Brunetto, Roesler Rafael
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.
Oncotarget. 2016 Jun 7;7(23):34860-80. doi: 10.18632/oncotarget.8992.
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.
尤因肉瘤（ES）是一种具有高度侵袭性的儿科癌症，可能起源于神经前体细胞。神经营养因子可刺激神经元发育和可塑性。在此，我们发现神经营养因子神经生长因子（NGF）和脑源性神经营养因子（BDNF）及其受体（分别为TrkA和TrkB）在ES肿瘤中表达。用TrkA（GW - 441756）或TrkB（Ana - 12）选择性抑制剂处理可降低ES细胞增殖，当两种抑制剂联合使用时效果增强。用泛Trk抑制剂K252a处理ES细胞后，细胞形态发生变化，β-III微管蛋白水平降低，NGF、BDNF、TrkA和TrkB的mRNA表达减少。此外，将K252a与亚有效剂量的细胞毒性化疗药物联合使用，即使在化疗耐药细胞中也能导致ES细胞增殖和集落形成减少。这些结果表明，抑制Trk可能是一种新兴的ES治疗方法。
