STUDY OF CYTOTOXIC ACTIVITY AND AUTOPHAGY INDUCTION BY COPPER(II) COMPLEXES IN MELANOMA CELL LINES WITH RESISTANCE PHENOTYPE TO BRAF INHIBITION

• Grant number: 23/02492-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2023
• End date: May 31, 2024
• Field of knowledge: Health Sciences - Pharmacy - Toxicological Analysis
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Yasmin Catharine da Paz Mendonça
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Due to its metastatic and highly proliferative capacity, melanoma is the skin cancer with the highest mortality rate, although it is a minor incident. This scenario is mainly due to the waiting aspect in the MAPK pathway, mainly in the BRAFV600E protein, which exacerbates signals of growth, survival, invasion, and blocking of cell death. In this sense, the development of BRAF inhibitors (BRAFi, for example, vemurafenib) has revolutionized the treatment of melanoma. However, through this therapy, selecting cells with the most modified resistance phenotypes promotes tumor repopulation and consequently fails in therapeutic success. Therefore, searching for new therapeutic alternatives that overcome these is still imperative. Mono- and dinuclear copper(II) complexes (CCu(II)) have been studied in the context of the doctoral thesis Manoel O. Moraes Jr. (FAPESP 2020/15042-4) with emphasis on the dinuclear CCu(II) for this purpose. This compound demonstrated cytotoxicity on human melanoma cell lines with and without iBRAF-resistance phenotype, triggering oxidative stress, DNA damage, and mitochondrial membrane depolarization with possible induction of autophagic process (unpublished preliminary data). However, it is still necessary to elucidate the consequences of promoting autophagy in these cells. Therefore, using cell viability assays, flow cytometry, fluorescence microscopy, and western blotting in a two- and three-dimensional experimental model, this project intends to study the induction of the autophagic process as part of the mechanism of action of dinuclear CCu(II), in order to understand and promote a viable alternative for the melanoma threatment with and/or without resistance phenotype to BRAF inhibitors.