Avaliação da atividade inibitória da proteína tipo Lisil oxidase 2 (LOXL2) de pimaranos e seus derivados glicosídicos
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2023
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Edições Universitárias Lusófonas
Resumo
A lisil oxidase (LOX) e as proteínas tipo lisil oxidase 1-4 (LOXL 1-4) catalisam a ligação cruzada de elastina e colagénio na matriz extracelular, facilitando a migração e invasão celulares. A inibição destas enzimas, particularmente LOXL2, tem sido sugerida como estratégia terapêutica para prevenir metástases do cancro da mama. Neste trabalho, novos inibidores naturais de LOXL2 foram investigados a partir de Aeollanthus rydingianus, uma planta medicinal rica em produtos bioativos. Cinco diterpenóides de pimarano, dois isolados da planta e três derivados foram testados. Estes compostos foram previamente descritos pelas suas propriedades bioativas, tais como antitumoral, anti-inflamatória, analgésica e antibacteriana. Neste sentido, pretendemos explorar os mecanismos destes compostos, estudando os seus efeitos na atividade da LOXL2. Dois diterpenóides pimaranos mostraram uma ligeira atividade inibitória da LOXL2, avaliada por uma técnica baseada no Amplex Ultra Red. A toxicidade do composto mais ativo foi analisada pelo ensaio MTT na linha celular MDA-MB-231, representativa do cancro da mama triplo negativo. Este composto diminuiu a viabilidade celular como agente isolado e aumentou o efeito citotóxico da doxorubicina. O seu glicoconjugado foi consideravelmente mais tóxico, provavelmente devido a uma maior captação pelas célula tumorais. Palavras-chave: cancro da mama, proteína tipo lisil oxidase 2, inibidores, pimaranos, Aeollanthus rydingianus, MTT
Lysyl oxidase (LOX) and LOX-like 1-4 (LOXL 1-4) enzymes catalyze the cross-linking of elastin and collagen in the extracellular matrix, facilitating cell migration and invasion. The inhibition of these enzymes, particularly LOXL2, has been suggested as a therapeutic strategy to prevent breast cancer metastasis. In this work, new natural LOXL2 inhibitors were searched from Aeollanthus rydingianus, a medicinal plant rich in bioactive products. Five pimarane diterpenoids, two isolated from the plant and three derivatives, were tested. These compounds have been described for their bioactive properties such as anti-tumor, anti-inflammatory, analgesic, and antibacterial activities. In this regard, we intended to explore the mechanisms of these compounds by studying their effects on LOXL2 activity. Two pimarane diterpenoids showed a mild LOXL2 inhibitory activity as evaluated by an Amplex Ultra Red-based technique. The cytotoxicity of the most active compound was analyzed by the MTT assay in the MDA-MB-231 cell line, representative of triplenegative breast cancer. This compound decreased cell viability as single agent and increased the cytotoxic effect of doxorubicin. Its glycoconjugate was considerably more toxic, likely due to a higher uptake by cancer cells. Keywords: breast cancer, lysyl oxidase-like 2, inhibitors, pimaranes, Aeollanthus rydingianus, MTT
Lysyl oxidase (LOX) and LOX-like 1-4 (LOXL 1-4) enzymes catalyze the cross-linking of elastin and collagen in the extracellular matrix, facilitating cell migration and invasion. The inhibition of these enzymes, particularly LOXL2, has been suggested as a therapeutic strategy to prevent breast cancer metastasis. In this work, new natural LOXL2 inhibitors were searched from Aeollanthus rydingianus, a medicinal plant rich in bioactive products. Five pimarane diterpenoids, two isolated from the plant and three derivatives, were tested. These compounds have been described for their bioactive properties such as anti-tumor, anti-inflammatory, analgesic, and antibacterial activities. In this regard, we intended to explore the mechanisms of these compounds by studying their effects on LOXL2 activity. Two pimarane diterpenoids showed a mild LOXL2 inhibitory activity as evaluated by an Amplex Ultra Red-based technique. The cytotoxicity of the most active compound was analyzed by the MTT assay in the MDA-MB-231 cell line, representative of triplenegative breast cancer. This compound decreased cell viability as single agent and increased the cytotoxic effect of doxorubicin. Its glycoconjugate was considerably more toxic, likely due to a higher uptake by cancer cells. Keywords: breast cancer, lysyl oxidase-like 2, inhibitors, pimaranes, Aeollanthus rydingianus, MTT
Descrição
Biomedical and biopharmaceutical research : jornal de investigação biomédica e biofarmacêutica
Palavras-chave
CIÊNCIAS FARMACÊUTICAS, CANCRO DA MAMA, ENZIMAS, PROTEÍNAS, PHARMACEUTICAL SCIENCES, BREAST CANCER, ENZYMES, PROTEINS
Citação
Ferreira, S, Rijo, P, Costa, J G, Saraiva, N, Santos, B, Uriel, C, Goméz, A M, Díaz-Lanza, A M & Fernandes, A S 2023, 'Avaliação da atividade inibitória da proteína tipo Lisil oxidase 2 (LOXL2) de pimaranos e seus derivados glicosídicos', Biomedical and biopharmaceutical research : jornal de investigação biomédica e biofarmacêutica.