BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity
- Biochemistry and Biophysics Laboratory, Butantan Institute, São Paulo, SP (Brazil)
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen (Netherlands)
- Laboratory of Drug Design and Development, University of São Paulo, São Paulo, SP (Brazil)
- Laboratory of Tumor Immunology, University of São Paulo, São Paulo, SP (Brazil)
- Laboratory of Cytopathology, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP (Brazil)
- Laboratory of Genetics, Butantan Institute, São Paulo, SP (Brazil)
- Experimental Oncology Section, The Federal University of São Paulo, São Paulo, SP (Brazil)
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. - Highlights: • 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.
- OSTI ID:
- 22687915
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 295; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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