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Resorcinolic lipid 3-heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one is a strategy for melanoma treatment

2018; Elsevier BV; Volume: 209; Linguagem: Inglês

10.1016/j.lfs.2018.08.022

1879-0631

Stephanie Dynczuki Navarro, Lucas Roberto Pessatto, Alisson Meza, Rodrigo Cardoso de Oliveira, Sarah Alves Auharek, Lízia Colares Vilela, Dênis Pires de Lima, Ricardo Bentes Azevedo, Cândida Aparecida Leite Kassuya, Osmar Ignacio Ayala Cáceres, Roberto da Silva Gomes, Adilson Beatriz, Rodrigo Juliano Oliveira, Marco António Utrera Martines,

Synthesis of Tetrazole Derivatives

Previous studies performed by our research group indicated that cytosporone analogues are capable of prevent or repair DNA damages. This work presents the evaluation of the activity of AMS35AA for metastatic murine melanoma cells (B16F10) in experimental model in vitro and, in pre-clinic assay of metastatic melanoma in vivo, using mice lineage C57BL/6. In vitro assays were performed: MTT and comet assay, flow cytometry evaluation, gene expression assay by RT-PCR, qualitative evaluation of cell death using B16F10 cells. In vivo assays: micronucleus and comet assay, splenic phagocytosis, melanoma murine model and histopathological analysis, using mice lineage C57BL/6 (n = 20). In vitro results performed by MTT assay showed that AMS35AA is cytotoxic for B16F10 cells (p < 0.05). Based on comet assay the genotoxicity of the IC50 was determined (95.83 μg/mL) (p < 0.05). These data were corroborated by flow cytometry analysis after the treatment with AMS35AA, which indicates the cellular death by apoptosis (p < 0.05) and increasing of ATR, p53, p21 and GADD45 gene expressions verified using RT-PCR. With respect to in vivo results, it was observed that AMS35AA did not show genotoxic activity. Data of tumor volume ex vivo indicate reduction of tumor for the treated animals with AMS35AA up to 15.84×, which is superior to Dacarbazina (50 mg/Kg, p.c.; i.p.). In summary, the study showed that AMS35AA reveals relevant results regarding to cytotoxicity of B16F10 murine melanoma cells, inducing death by apoptosis via mitochondrial and/or mediated by DNA damages.