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Evaluation of the potential for overcoming melanoma chemoresistance to BRAF V600E (Vemurafenib) and MEK (Trametinib) inhibitors using combined therapy with 4-nerolidylcatechol (4-NC)

Grant number: 14/06959-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2014
Effective date (End): July 01, 2018
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Silvya Stuchi Maria-Engler
Grantee:Débora Kristina Alves Fernandes
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/07010-2 - Effect of the aged-related changes in tumor microenvironment in the angiogenesis and lymphangiogenesis, BE.EP.DR

Abstract

Melanoma accounts for only 4% of skin malignancies, but is considered the most serious one as it takes the patient to death in a few months. Because MAPK pathway is closely related to uncontrolled cell proliferation, especially in melanoma, this route has become a target for the development of oncogene targeted therapies. Such is the case of the potent chemotherapeutic drugs Vemurafenib (BRAFV600E inhibitor) and Trametinib (MEK inhibitor), which have been recently developed and is already considered a hope for patients with melanoma. Very high response rates have been achieved with these drugs, which shows the revolution generated from treatment with specific inhibitors in advanced melanoma patients. However, most patients are subject to resistance and show relapse after 7 months of treatment due to various mechanisms, justifying the constant search for new therapeutic compounds that can overcome or minimize chemoresistance, thus effectively lead to a cure. Recent data from our laboratory indicated that 4-nerolidylcatechol (4-NC) induces caspase-3-dependent apoptosis in melanoma cells by increased production of ROS, DNA damage and increased p53 expression. , and it is a potent time-dependent proteasome inhibitor of Noxa and Mcl- 1 proteins. 4-NC also demonstrated an inhibitory effect on the proliferation of melanoma cells in the organotypic culture model of artificial skin. In this proposal we aim to evaluate the possibility of overcoming chemoresistance to BRAF and MEK inhibitors, using combined therapies with 4-NC in human melanoma cells resistant to these drugs. For this purpose, we will develop new strains of human melanoma cells resistant to the inhibitors Vemurafenib and Trametinib.The resistance profile will be confirmed by the MTT cell viability assay and western blotting and the cytotoxicity of the combined therapy will be evaluated through trypan blue assay. Genotoxicity will be evaluated through assessment of membrane integrity, DNA damage and fragmentation. The investigation of possible mechanisms of cytotoxicity will be performed through investigation of proteasome activity, autophagy and senescence. Finally, we will analyze the interference of the combined therapy in cases of invasion and cell migration in three-dimensional and monolayer models, respectively. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIRA, ERICA APARECIDA; HASTREITER, ARACELI APARECIDA; FAIAO-FLORES, FERNANDA; FELIPE-SILVA, ALOISIO SOUZA; TURATO, WALTER; FOCK, RICARDO AMBROSIO; MARIA-ENGLER, SILVYA STUCHI; DE MORAES BARROS, SILVIA BERLANGA. In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma. Food and Chemical Toxicology, v. 141, JUL 2020. Web of Science Citations: 0.
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIR, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; ALICEA-REBECCA, GRETCHEN; WEERARATNA, ASHANI T.; SMALLEY, KEIRAN S. M.; DE MORAES BARROS, SILVIA BERLANGA; MARIA-ENGLER, SILVYA STUCHI. ER stress promotes antitumor effects in BRAFi/MEKi resistant human melanoma induced by natural compound 4-nerolidylcathecol (4-NC). PHARMACOLOGICAL RESEARCH, v. 141, p. 63-72, MAR 2019. Web of Science Citations: 1.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.