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

Autor(es):Mostrar menos -

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]

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

• 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: 09/54599-5 - Células dendríticas: elementos integrados do sistema imune - enfoque aplicado
• Beneficiário: Jose Alexandre Marzagão Barbuto
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• 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
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• 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
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• 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
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado