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EVALUATION OF NOVEL DUAL HISTONE DESACETYLASE AND METALLOPROTEINASE INHIBITORS IN GLIOBLASTOMA CELL LINES

Grant number: 23/00454-3
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2023
Effective date (End): June 30, 2024
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Leticia Veras Costa Lotufo
Grantee:Leticia Marcelino Gouvêa
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/50926-0 - INCT 2014: biodiversity and natural products, AP.BTA.TEM

Abstract

Cancer is the term used to designate a set of diseases that are characterized by the disordered growth of somatic cells, caused by an accumulation of multiple genetic and epigenetic mutations that give the cells the capacity for tissue invasion and metastasis. It is a multifactorial disease resulting from the interaction of different factors that promote carcinogenesis. Gliomas are Central Nervous System (CNS) tumors that affect mainly the adult population and impose a low survival rate on patients diagnosed with such, being glioblastoma the most aggressive subtype, presenting a poor prognosis after diagnosis. Given this scenario, the demand for new therapies is urgent. To explore new molecular targets for the treatment of this disease, the aim of this project is to evaluate the cytotoxic potential of new synthetic compounds designed based on the histone deacetylase (HDAC) inhibitor PCI-34051 and the metalloproteinase inhibitor CGS-25966, and thus, the potential ability to inhibit both enzymes. The use of dual inhibitors has been seen as a strategy to improve the effectiveness of antitumor substances in addition to reducing adverse effects of combinations of different drugs. Initially, the activity of the substances on the target enzymes HDAC and MMPs will be validated through enzymatic assays. Then, the compounds will be evaluated through the Sulforhodamine B assay to access their cytotoxic potential in glioblastoma cell lines, U87MG and U251MG, followed by studies on the mechanisms involved in their toxicity, using different techniques, including clonogenic assay, flow cytometry, wound healing assay, and also markers to identify the expression of cell death and tissue invasion proteins, such as caspases 3, 8 and 9, metalloproteinases MMP2 and MMP9, n-cadherin and vimentin. In this way, we intend to evaluate the potential of these new compounds and the possible epigenetic modulations as a therapy for this type of cancer.

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