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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity

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Autor(es):
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Ferreira, Adilson Kleber [1, 2] ; Mesquita Pasqualoto, Kerly Fernanda [3] ; Kruyt, Frank A. E. [2] ; Palace-Berl, Fanny [4] ; Azevedo, Ricardo Alexandre [1] ; Turra, Kely Medeiros [5] ; Rodrigues, Cecilia Pessoa [1] ; Franco Ferreira, Ana Carolina [1] ; Clavijo Salomon, Maria Alejandra [1] ; de Sa Junior, Paulo Luiz [6] ; Farias, Camyla Fernandes [7] ; Figueiredo, Carlos Rogerio [7] ; Tavares, Leoberto Costa [4] ; Marzagdo Barbuto, Jose Alexandre [1, 8] ; Jorge, Salomao Doria [1]
Número total de Autores: 15
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Lab Tumor Immunol, Sao Paulo, SP - Brazil
[2] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Hanzepl 1, Groningen - Netherlands
[3] Butantan Inst, Biochem & Biophys Lab, Sao Paulo, SP - Brazil
[4] Univ Sao Paulo, Lab Drug Design & Dev, Sao Paulo, SP - Brazil
[5] Univ Sao Paulo, Lab Cytopathol, Dept Clin Chem & Toxicol, Fac Pharmaceut Sci, Sao Paulo, SP - Brazil
[6] Butantan Inst, Genet Lab, Sao Paulo, SP - Brazil
[7] Univ Fed Sao Paulo, Expt Oncol Sect, Sao Paulo, SP - Brazil
[8] Univ Sao Paulo, Cell & Mol Therapy Ctr NUCEL NETCEM, Sao Paulo, SP - Brazil
Número total de Afiliações: 8
Tipo de documento: Artigo Científico
Fonte: Toxicology and Applied Pharmacology; v. 295, p. 56-67, MAR 15 2016.
Citações Web of Science: 6
Resumo

Benzofuroxan is an interesting ring system, which has shown a wide spectrum of biological responses against tumor cell lines. We investigated, herein, the antitumor effects of benzofuroxan derivatives (BFDs) in vitro and in a melanoma mouse model. Cytotoxic effects of twenty-two BFDs were determined by MIT assay. Effects of BFD-22 in apoptosis and cell proliferation were evaluated using Annexin V-FITC/PI and CFSE staining. In addition, the effects in the cell cycle were assessed. Flow cytometry, western blot, and fluorescence microscopy analysis were employed to investigate the apoptosis-related proteins and the BRAF signaling. Cell motility was also exploited through cell invasion and migration assays. Molecular docking approach was performed in order to verify the BFD-22 binding mode into the ATP catalytic site of BRAF kinase. Moreover, the BFD-22 antitumor effects were evaluated in a melanoma murine model using B16F10. BFD-22 was identified as a potential hit against melanoma cells. BFD-22 induced apoptosis and inhibited cell proliferation of B16F10 cells. BFD-22 has suppressed, indeed, the migratory and invasive behavior of B16F10 cells. Cyclin D1 and CDK4 expression were reduced leading to cell cycle arrest at G0/G1 phase. Of note, phosphorylation of BRAF at Ser338 was strongly down-regulated by BFD-22 in B16F10 cells. The accommodation/orientation into the binding site of BRAF was similar of BAY43-9006 (co-crystallized inhibitor of BRAF, sorafenib). Importantly, BFD-22 presented in vivo antimetastatic effects and showed better therapeutic efficacy than sorafenib and taxol. BFD-22 can be considered as a new lead compound and, then, can be helpful for the designing of novel drug candidates to treat melanoma. (C) 2016 Elsevier Inc. All rights reserved. (AU)

Processo FAPESP: 14/07341-0 - Avaliação dos efeitos antitumorais de um novo fosfolipídio antitumoral análogo como inibidor da enzima CTP: citidililtransferase fosfoetanolamina em câncer de pulmão de não pequenas células
Beneficiário:Adilson Kleber Ferreira
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
Processo FAPESP: 13/05396-0 - Planejamento racional e desenvolvimento de novos protótipos derivados de fosfolipídios antitumorais como inibidores potenciais da enzima CTP:fosfoetanolamina citidililtransferase e agentes antitumorais em carcinoma de pulmão do tipo não pequenas células
Beneficiário:Adilson Kleber Ferreira
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/14267-1 - Agentes antitumorais potencialmente multialvos para melanoma: planejamento racional, síntese e ensaio biológico de novos derivados benzofuroxanos
Beneficiário:Salomão Dória Jorge
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 09/54599-5 - Células dendríticas: elementos integrados do sistema imune - enfoque aplicado
Beneficiário:Jose Alexandre Marzagão Barbuto
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/07273-2 - Planejamento racional e desenvolvimento de novos protótipos derivados de fosfolipídios antitumorais como inibidores potenciais da enzima CTP: fosfoetanolamina citidililtransferase e agentes antitumorais em carcinoma de pulmão de não pequenas células
Beneficiário:Jose Alexandre Marzagão Barbuto
Linha de fomento: Auxílio à Pesquisa - Regular