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Comparative evaluation of antitumor effects of NF-ºB inhibitors DHMEQ, DTCM-g and SEMBL in Ewing's Sarcoma

Grant number: 19/17020-0
Support type:Scholarships in Brazil - Master
Effective date (Start): December 01, 2019
Effective date (End): June 30, 2021
Field of knowledge:Biological Sciences - Biology
Principal Investigator:María Sol Brassesco Annichini
Grantee:Mariana Medeiros
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Childhood cancer is among the leading causes of death in children and adolescents between 0 and 19 years and among them, Ewing's sarcoma is responsible for the death of 2.4 children on average every 1,000,000 every year. This is a very aggressive cancer with high relapse rates. Current treatment is mainly based on a cocktail of chemotherapy drugs, but in many cases the tumor has resistance. For this reason the search for new therapeutic targets is necessary. A good candidate is nuclear transcription factor kappa B (NF-ºB) which is involved in several oncogenic pathways as a regulator of genes related to increased proliferation, survival, migration and invasion, as well as anti-apoptotic genes. In recent years, the research group of Prof. Umezawa (Aichi University, Japan) has developed 3 NF-ºB inhibitors: DHMEQ, DTCM-g and SEMBL, which have already been shown to be effective against both in vitro and in vivo tumor cells without presenting animal side effects or cytotoxicity in non-malignant cells. . Thus, the present study aims to perform a comparative analysis of the in vitro effects of inhibition of NF-ºB transcription factor on Ewing's sarcoma cell lines by DHMEQ, DTCM-g and SEMBL inhibitors. For this, RD-ES and SK-ES-1 cell lines will be cultured in monolayer and 3D models and exposed to different concentrations of DHMEQ, DTCM-g and SEMBL associated or not with doxorubicin. In parallel, tests will be performed to evaluate the activation state of NF-ºB, cytotoxicity, migration, invasion, clonogenic capacity and an analysis of the expression of genes involved in all these processes and in chemoresistance and immunohistochemistry for proliferation markers, apoptosis and invasion. All tests will be performed in triplicate, analyzed using GraphPad Prism 7 software (GraphPad, USA) and differences will only be considered significant when p <0.05.