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In vitro, in vivo and in silico studies of the antineoplastic activity of formononetine in melanoma

Grant number: 18/25770-7
Support type:Scholarships in Brazil - Master
Effective date (Start): April 01, 2019
Effective date (End): February 28, 2021
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Denise Crispim Tavares Barbosa
Grantee:Arthur Barcelos Ribeiro
Home Institution: Pró-Reitoria Adjunta de Pesquisa e Pós-Graduação. Universidade de Franca (UNIFRAN). Franca , SP, Brazil
Associated research grant:17/04138-8 - Attainment of chemical, analytical, biological, pharmacological and technological studies to fill the gaps on the development of Brazilian propolis sector, AP.TEM

Abstract

Melanoma (MLA) has a heterogeneous and complex etiology resulting from the interaction of genetic, immunological and environmental factors, which play essential roles in all phases of its development. The best therapeutic responses for the treatment of MLA it is based on the infusion of cytotoxic drugs, limited by immunosuppression, resistance and high toxicity. Several molecular alterations involved in the initiation and progression of MLA have been elucidated. However, advances in therapy are still limited. In the search for new molecules for treatment, as well as in reducing the side effects of existing treatments, products of natural origin are highlighted in cancer chemotherapy and can be used in treatments alone or combined with other antineoplastics. In this way, O-methylated isoflavone, formononetine (FOR), a biomarker of extracts of Brazilian red propolis, presents promising antiproliferative activity. In addition to the various biological activities reported in the literature as anti-inflammatory, antidiabetic, analgesic and antimicrobial, most studies with FOR are based on cytotoxic assays against a wide range of tumor cell lines. In view of the above assessment, the present work aims to evaluate the antitumor activity of FOR in MLA. For this purpose, functional assays of cell morphology, proliferation, clonogenicity, apoptosis, cell cycle, adhesion and migration after treatment with FOR isolated and combined with cisplatin and dacarbazine chemotherapeutic agents in murine (B16-F10) and human (A-375) melanoma cell lines.Additionally, in vivo studies will be conducted aiming to evaluate the antitumor activity of FOR in a murine melanoma model using the B16-F10 cell line, whose parameters of antitumor activity (angiogenesis, histology of the tumor, liver and lung, and volume, weight and tumor control index) and toxicological factors (weight, water consumption, animal survival, biochemical dosages and genotoxicity) will be analyzed. In order to better understand the mechanisms of action of FOR in MLA, evaluations of gene expression in apoptotic signaling pathways and in silico interaction studies between FOR and signaling pathways proteins of MLA cell proliferation will be performed. This research may provide insights into the identification of new therapeutic strategies for the treatment of MLA.