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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 12
Affiliation:
[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
Total Affiliations: 6
Document type: Journal article
Source: FRONTIERS IN MARINE SCIENCE; v. 8, MAY 3 2021.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 18/24865-4 - New approaches in metabolomics: 3D Molecular cartography of ascidians based on LC-MS/MS data
Grantee:Anelize Bauermeister
Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 17/18235-5 - Anticancer potential of isolated substances from Streptomyces SP. recovered from ascidian Euherdmania SP
Grantee:Luciana Costa Furtado
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
Grantee:Leticia Veras Costa Lotufo
Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
FAPESP's process: 17/17648-4 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
Grantee:Anelize Bauermeister
Support Opportunities: Scholarships in Brazil - Post-Doctoral