Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

Autor(es):Mostrar menos -

Furtado, Luciana C. ^[1] ; Bauermeister, Anelize ^{[1, 2]} ; de Felicio, Rafael ^[3] ; Ortega, Raquel ^[3] ; Pinto, Francisco das Chagas L. ^[4] ; Machado-Neto, Joao Agostinho ^[1] ; Trivella, Daniela B. B. ^[3] ; Pessoa, Otilia D. L. ^[4] ; Wilke, Diego V. ^[5] ; Lopes, Norberto P. ^[2] ; Jimenez, Paula C. ^[6] ; Costa-Lotufo, Leticia V. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Farmacol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Quim & Fis, NPPNS, Ribeirao Preto - Brazil

^[3] Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias, Campinas - Brazil

^[4] Univ Fed Ceara, Dept Quim Organ & Inorgan, Fortaleza, Ceara - Brazil

^[5] Univ Fed Ceara, Dept Fisiol & Farmacol, Nucleo Pesquisa & Desenvolvimento Medicamentos, Fortaleza, Ceara - Brazil

^[6] Univ Fed Sao Paulo, Inst Mar, Santos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN MARINE SCIENCE; v. 8, MAY 3 2021.
• Citações Web of Science: 0

Resumo

Marine natural products have emerged as an important source for drug development, notably in the field of anticancer therapy. Still, the limited effectiveness of current therapies for central nervous system tumors indicates the need to identify new therapeutic targets and also novel pharmacological agents. In this context, proteasome inhibitors are appearing as a promising new treatment for these diseases. Herein, cytotoxic extracts produced by four marine bacteria recovered from the Brazilian endemic ascidian Euherdmania sp. were screened to evaluate their potential as proteasome inhibitors. The extract from marine Streptomyces sp. BRA-346 was selected for further investigation due to the potent proteasome inhibitory activity it displayed. Bioassay-guided fractionation led to an enriched fraction (proteasome inhibition IC50 = 45 ng/mL), in which the presence of dihydroeponemycin (DHE), known for its proteasome inhibitory effect, and related compounds were annotated by mass spectrometry and further confirmed by comparison with DHE standard. Both DHE and the epoxyketone-containing fraction were evaluated in glioma cell lines, displaying high cytotoxicity in HOG and T98G cells (GI(50) of 1.6 and 1.7 ng/mL for DHE, and 17.6 and 28.2 ng/mL for the BRA-346 fraction, respectively). Additional studies showed that the epoxyketone-containing fraction (at GI(50) levels) led to an accumulation of ubiquitinated proteins and up-regulation of genes related to ER-stress response, suggesting treated cells are under proteasome inhibition. DHE induced similar effects in treated cells but at concentrations 25 times its GI(50), suggesting that the other epoxyketone compounds in the bacteria extract derived fraction may contribute to enhance proteasome inhibition and further cellular effects in glioma cells. These findings revealed the molecular pathways modulated by this class of compounds in glioma cells and, moreover, reinforced the potential of this marine bacteria in producing a cocktail of structurally-related compounds that affect the viability of glioma cells. (AU)

• Processo FAPESP: 18/24865-4 - Novas abordagens em metabolomica: Cartografia Molecular 3D de ascídias baseado em dados de LC-MS/MS
• Beneficiário: Anelize Bauermeister
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 17/18235-5 - Potencial anticâncer de substâncias isoladas de Streptomyces SP. recuperada da Ascídia Euherdmania SP
• Beneficiário: Luciana Costa Furtado
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 15/17177-6 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
• Beneficiário: Leticia Veras Costa Lotufo
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 17/17648-4 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
• Beneficiário: Anelize Bauermeister
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado