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.
Histone deacetylase inhibitors and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, particularly when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been systematically evaluated in Ewing sarcoma. The in vitro effects on cellular proliferation, viability and survival were investigated in two Ewing sarcoma cell lines, SK-ES-1 and RD-ES. The cell lines were treated with sodium butyrate, a histone deacetylase inhibitor and zoledronic acid, a bisphosphonate, alone, together or in combination with chemotherapeutic drugs recommended for clinical treatment of Ewing sarcoma. The data demonstrated that the combination of sodium butyrate and zoledronic acid had a synergistic cytotoxic effect at 72 h following treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between sodium butyrate or zoledronic acid and the traditional antineoplastic drugs (doxorubicin, etoposide and vincristine) demonstrated a synergistic cytotoxic effect at 72 h in SK-ES-1 and RD-ES cells, except for the combinations of sodium butyrate with vincristine and of zoledronic acid with doxorubicin, which showed only an additive effect in RD-ES cell lines as compared to each agent alone. These acute effects observed in both Ewing sarcoma cell lines were confirmed by the clonogenic assay. The present data suggest that combining histone deacetylase inhibitors and bisphosphonates with traditional chemotherapeutic drugs is a promising therapeutic strategy for the treatment of Ewing sarcoma, and provides a basis for further studies in this field.
ResumoEste estudo tem como objetivo investigar a relação entre a perda auditiva e a exposição ocupacional ao ruído e ao tolueno. A população em estudo foi composta por 73 trabalhadores de curtume. Para conhecer a história clínica e ocupacional dos trabalhadores, aplicou-se um questionário. Para avaliação da exposição ocupacional, realizaram-se avaliações ambiental e biológica do tolueno e avaliações audiológica e dos níveis de ruído. Os valores obtidos na avaliação ambiental e biológica estavam abaixo dos limites estabelecidos pelas NR 7 e 15. Os níveis de ruído em diversos setores da indústria foram superiores ao máximo permitido pela NR 15, chegando a 97.8 dB(A). As perdas auditivas encontradas no grupo ruído (GR) e no grupo ruído e agente químico (GRAQ) foram significativas quando comparadas ao grupo controle através da análise estatística SPSS ® , T-Test p<0,01. Este estudo demonstrou fatores de impacto na saúde e na qualidade de vida dos trabalhadores. Portanto, fazem-se necessárias a revisão dos programas e a implementação de medidas que reduzam os riscos de forma a prevenir e evitar danos à saúde do trabalhador.
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