Neolignans isolated from Nectandra leucantha induce apoptosis in melanoma cells by disturbance in mitochondrial integrity and redox homeostasis

Autor(es)

de Sousa, Fernanda S. ; Grecco, Simone S. ; Girola, Natalia ; Azevedo, Ricardo A. ; Figueiredo, Carlos R. ; Lago, Joao Henrique G.

• Tipo de documento: Artigo Científico
• Fonte: Phytochemistry; v. 140, p. 108-117, AUG 2017.
• Citações Web of Science: 8

Resumo

Six neolignans including three previously undescribed metabolites: 1-{[}(7R)-hydroxy-8-propeny1]-3-{[}3'-methoxy-1'-(8'-propeny1)-phenoxy]- 4,5-dimethoxybenzene, 4-hydroxy-5-methoxy-3-{[}3'-methoxy-1'-(8'-propenyl)phenoxyl-1-(7-oxo-8- propenyl)benzene and 4,5-dimethoxy-3-{[}3'-methoxy-1'-(8'-propenyl)phenoxy]-1-(7-oxo-8-propen yl)benzene were isolated from twigs of Nectandra leucantha Nees \& Mart (Lauraceae) using bioactivity-guided fractionation. Cytotoxic activity of isolated compounds was evaluated in vitro against cancer cell lines (SR BR-3, HCT, U87-MG, A2058, and B16F10), being dehy-drodieugenol B and 4-hydroxy-5-methoxy-3-{[}3'-methoxy-1'-(8'-propenyl)phenoxy]-1-(7-oxo-8- propenyl)benzene the most active metabolites. These compounds displayed IC50 values of 78.8 +/- 2.8 and 82.2 +/- 3.5 mu M, respectively, against murine melanoma. Different in vitro mechanism of induced cytotoxicity for this cell line is proposed for both compounds. Obtained results indicated a remarkable effect during the induction of morphological, biochemical and enzymatic features of apoptosis, such as disruption of mitochondrial membrane potential (Delta Psi m), exposure of phosphatidylserine in the outer cell membrane, and-genomic DNA condensation and fragmentation. Dehydrodieugenol B induced caspase-3 and PARP activation and 4-hydroxy-5-methoxy-3-{[}3'-methoxy-1'-(8'-propenyl)phenoxy]-1-(7-oxo-8- propenyl)benzene downregulated the levels of Bcl-2 protein. These effects were accompanied by increased levels of reactive oxygen species as a consequence of mitochondrial damage, followed by F-actin aggregation during the cell death process. Dehydrodieugenol B showed oxidative properties and both compounds, especially 4-hydroxy-5-methoxy-3-{[}3'-methoxy-1'-(8'-propenyl)phenoxyl-1-(7-oxo-8- propenyl)benzene, displayed potential to alkylate nucleophiles, suggesting an accessory mechanism of tumor-induced cytotoxicity by these metabolites. (C) 2017 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 15/04143-6 - Metabólitos naturais e semissintéticos dos galhos de Nectandra leucantha Ness & Mart. (Lauraceae): caracterização molecular e avaliação do potencial e mecanismo antitumoral contra melanoma
• Beneficiário: Fernanda Samara de Sousa
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 15/11936-2 - Emprego da quimiodiversidade de espécies vegetais de áreas remanescentes da Mata Atlântica do Estado de São Paulo na seleção de protótipos biologicamente ativos
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Regular