Antiproliferative and cell invasion inhibitor potencial of new copper (II) complexes in human Melanoma with resistance to BRAF inhibitors phenotype

• Grant number: 20/15042-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): August 01, 2021
• Effective date (End): November 30, 2024
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Manoel Oliveira de Moraes Junior
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/04926-6 - Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets, AP.TEM

Abstract

Melanoma is a Cancer with high mortality rates and high metastatic capacity, resulting from mutations in several genes that confer phenotypic changes, with emphasis on changes in the MAPK signaling pathway especially the mutation in the BRAF protein (V600E). In addition to the use of DNA alkylating drugs, target therapy is already used in the clinics, in which is represented by drugs that inhibit molecules relevant to carcinogenesis, such as BRAF inhibitors (iBRAF, eg vemurafenib). However, after 6 months, a considerable number of patients begin to show signs of resistance to iBRAF molecules. Thus, many candidates for prototypes of metallodrugs have been investigated regarding their anticancer profile, including on Melanoma models. Copper (II) complexes have already been reported regarding their ability to trigger programmed cell death in cancer cells, including pleading for an activity with fewer expected adverse effects. Professor Ana Maria da Costa Ferreira's research group has expertise in the development of bioactive metal complexes, including the development of copper (II) with anticancer activity. Thus, Nunes and collaborators (2015, 2019) reported the design, synthesis and evaluation of dinuclear copper (II) complexes on Melanoma cell lines, where they showed cytotoxic activity with apoptotic and autophagic profile, but their effects on cells resistant to iBRAF have not been investigated yet. Therefore, this project aims to evaluate the cytotoxic activity and the mechanism of action of the dinuclear copper (II) complex (Cu2 (apyhist) 2 (dpam)] ClO4) in monolayer and organotypic cell model containing resistant to iBRAF (vemurafenib) cell lines. (AU)