Potencial anticâncer de substâncias isoladas de Streptomyces sp. recuperada da ascídia Euherdmania sp.

Author(s)

Luciana Costa Furtado

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2019-06-06

Examining board members

Leticia Veras Costa Lotufo; Catarina Raposo Dias Carneiro; João Agostinho Machado Neto; Regina Pekelmann Markus

• Advisor: Leticia Veras Costa Lotufo

Abstract

Marine natural products emerge as a source of inestimable pharmacological potential. In this perspective, the sustainable supply of bioactive metabolites from the cultivation of marine microorganisms appears as an attractive solution for the rational exploration of these substances. An initial screening with five marine bacterial extracts (BRA-339, BRA-341, BRA-346, BRA-374 and BRA-386) showed that, besides of the high cytotoxic potential, one of them (BRA-346) inhibited the catalytic activity of the ChTL subunit of the proteasome. The bacterium BRA-346 isolated from the Brazilian endemic ascidian, Euherdmania sp., was shown to be a promising source of cytotoxic substances. This strain, belonging to the genus Streptomyces, produces extract with significant cytotoxic activity, presenting IC50 of 30 ng/mL in human colon carcinoma cells, HCT-116. The enzymatic assay using purified S. cerevisiae proteasome showed an inhibition with an average concentration of 0.42 <font face = \"symbol\">mg/mL for the extract and 0.045 <font face = \"symbol\">mg/mL for its enriched fraction (BRA-346ADC). The crystallographic assays detected the presence of a compound belonging to the epoxy-ketone class bounded to the catalytic subunit ChTL. Mass spectrometric analysis identified the TMC-86A ion and dihydroeponemycin in the fraction. Proteasome inhibitors are used clinically in the treatment of multiple myeloma, but they have been tested with promising results in other types of cancers, including gliobastomas. This cancer still needs more effective therapy that allows a greater survival of the patients. Tests with the enriched fraction BRA-346 exhibited high cytotoxicity in the cell lines HOG (oligodendroglioma) and T98G (glioblastoma), IC50= 25.4 and 37.3 ng/mL, respectively. Analysis of the protein and genes expression related to the proteasome pathway and reticulum stress showed an increase of the ubiquitination and reticulum stress response genes induced by the BRA-346ADC fraction in the treatments. Together these results reinfornce the importance of the compounds present in the Streptomyces sp. BRA-346 in Glioblastoma models. (AU)

• 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