In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma

Author(s)

Alves-Fernandes, Debora Kristina ^[1] ; de Oliveira, Erica Aparecida ^{[1, 2]} ; Hastreiter, Araceli Aparecida ^[3] ; Faiao-Flores, Fernanda ^{[1, 2]} ; Felipe-Silva, Aloisio Souza ^[4] ; Turato, Walter ^{[1, 2]} ; Fock, Ricardo Ambrosio ^[3] ; Maria-Engler, Silvya Stuchi ^{[1, 2]} ; de Moraes Barros, Silvia Berlanga ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Skin Biol Grp, Ave Prof Lineu Prestes 580, BR-05508000 Sao Paulo - Brazil

^[2] Felipe-Silva, Aloisio Souza, Univ Sao Paulo, Fac Med FMUSP, Dept Pathol, Sao Paulo, Brazil.Alves-Fernandes, Debora Kristina, Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Skin Biol Grp, Ave Prof Lineu Prestes 580, BR-05508000 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Lab Hematol, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med FMUSP, Dept Pathol, Sao Paulo - Brazil

• Document type: Journal article
• Source: Food and Chemical Toxicology; v. 141, JUL 2020.
• Web of Science Citations: 0

Abstract

NRAS-mutations arise in 15-20% of all melanomas and are associated with aggressive disease and poor prognosis. Besides, the treatment for NRAS-mutant melanoma are not very efficient and is currently limited to immune checkpoints inhibitors or aggressive chemotherapy. 4-nerolidylcathecol (4-NC), a natural product extracted from Pothomorphe umbellata, induces apoptosis in melanoma cells by ROS production, DNA damage and increased p53 expression, in addition to inhibiting invasion in reconstructed skin. Moreover, 4-NC showed cytotoxicity in BRAF/MEKi-resistant and naive melanoma cells by Endoplasmic Reticulum (ER) stress induction in vitro. We evaluated the in vivo efficacy and the systemic toxicity of 4-NC in a NRAS-mutant melanoma model. 4-NC was able to significantly suppress tumor growth 4-fold compared to controls. Cleaved PARP and p53 expression were increased indicating cell death. As a proof of concept, MMP-2 and MMP-14 gene expression were decreased, demonstrating a possible role of 4-NC in melanoma invasion inhibition. Toxicological analysis indicated minor changes in the liver and bone marrow, but this toxicity was very mild when compared to other proteasome inhibitors and ER stress inductors already described. Our data indicate that 4-NC can counteract melanoma growth in vivo with minor adverse effects, suggesting further investigation as a potential NRAS-mutant melanoma treatment. (AU)

• FAPESP's process: 17/07010-2 - Effect of the aged-related changes in tumor microenvironment in the angiogenesis and lymphangiogenesis
• Grantee: Débora Kristina Alves Fernandes
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/24400-0 - In vitro models for pre clinical studies of melanoma Chemoresistant
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/06959-0 - Evaluation of the potential for overcoming melanoma chemoresistance to BRAF V600E (Vemurafenib) and MEK (Trametinib) inhibitors using combined therapy with 4-nerolidylcatechol (4-NC)
• Grantee: Débora Kristina Alves Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/04926-6 - Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Research Projects - Thematic Grants