Details

Autor(en) / Beteiligte

• Ferreira, Adilson Kleber
• Pasqualoto, Kerly Fernanda Mesquita
• Kruyt, Frank A.E.
• Palace-Berl, Fanny
• Azevedo, Ricardo Alexandre
• Turra, Kely Medeiros
• Rodrigues, Cecilia Pessoa
• Ferreira, Ana Carolina Franco
• Salomón, Maria Alejandra Clavijo
• de Sá, Paulo Luiz
• Farias, Camyla Fernandes
• Figueiredo, Carlos Rogerio
• Tavares, Leoberto Costa
• Barbuto, José Alexandre Marzagão
• Jorge, Salomão Dória

Titel

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

Ist Teil von

• Toxicology and applied pharmacology, 2016-03, Vol.295, p.56-67

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 MTT 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. •BFD-22 induces apoptosis effects of B16F10 cells by mitochondrial pathway.•BFD-22 provokes downstream in the MAPK/ERK kinase signaling cascade.•Molecular docking trials supported BRAF protein as potential target for BDF-22.•BFD-22 increases the therapeutic tumor immunogenicity.•BFD-22 presents stronger in vivo anti-metastatic effects than sorafenib and taxol.