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Characterization of seriniquinone mechanism of action in vemurafenibe resistant Melanoma cells

Grant number: 20/06613-8
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2020
Effective date (End): October 31, 2023
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal researcher:Leticia Veras Costa Lotufo
Grantee:Amanda Soares Hirata
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds, AP.BTA.TEM

Abstract

The most aggressive Skin Cancers is Melanoma, which has a high mortality rate and increasing incidence. The BRAFV600E protein ihibitors, the most recurrent mutation in Melanoma, came at the beginning of the decade as promising treatments, however, the high cost, adverse effects and frequent tumor resistance are limiting its therapeutic success. Given this, there is an urgent need to discover new drugs for this type of Cancer. Seriniquinone (SQ) was isolated from the marine bacterium Serinicoccus sp. and it showed selective cytotoxicity for melanoma cells at nM concentrations. The same study also found that SQ binds to dermicidin protein (DCD), modulating its expression, generating death by autophagy followed by apoptosis. Our preliminary results showed that vemurafenib (PLX4032) resistant melanoma cells remain sensitive to SQ treatments. This way, SQ becomes a promising alternative in the treatment of resistant cells. The present project aims to characterize the antitumor activity of SQ in PLX4032 resistant cells, comparing it with its synthetic derivative LT406, and the effects on cell death pathways and on the DCD expression. For better understanding of mechanism of action, the analysis of the transcriptome and proteome of the treated cells and controls will be carried out, seeking to understand the role of dermicidin in SQ and LT406 activity and in resistance to PLX4032. In addition, the study of compounds in 3D models of cellular spheroids and reconstructed skin in vitro is planned as a strategy to evaluate their actions in models that best represent the complexity of the tumor environment. (AU)