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Investigation of the multiple chemotherapy resistance phenotype in glioblastoma cell lines and its relationship with the Rho GTPases pathway

Grant number: 23/04220-7
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2023
Effective date (End): November 30, 2023
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Fábio Luis Forti
Grantee:Caroline Abe dos Santos
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and frequently diagnosed type of brain tumor among glioma subtypes. The treatments begin with radio and chemotherapy and, when it's possible, with the surgical resection of the tumor before or as an adjunct to the treatments. In addition to ionizing gamma radiation (IR), the main drug used in chemotherapy against these tumors is the temozolomide (TMZ), which promotes alkylations in DNA bases that are extremely toxic to cells. However, tumor recurrence is frequent in GBM patients and, when this occurs, tumor cells return resistant to previously used treatments. Several treatment alternatives and ways to minimize the acquired resistance of such cells to the usual therapies occur, in their majority, through the modulation of DNA recognition, signaling and repair mechanisms. Previous studies by our group have shown that TMZ resistant GBM cells are also resistant to cisplatin (PT), even without ever having been exposed to the drug. Furthermore, inhibition of the Rho GTPase pathway and actin cytoskeleton dynamics has been seen to reverse the chemoresistance phenotype of such cells. The purpose of this project is to verify whether such resistant individuals present characteristics of multiple resistance to different drugs with different mechanisms of action, such as Mitomycin C (MMC), Camptothecin (CPT) and Doxorubicin (DOX). From this, it will be possible to investigate the relationship between the resistance acquired by cells by different chemotherapeutic agents with the inhibition of the Rho GTPase pathway, a pathway that has been verified as a potential therapeutic target for tumor sensitization. A greater understanding of the action of other chemotherapeutic drugs and their combination with new therapies that sensitize and/or inhibit tumor progression are challenges of clinical interest for the treatment of GBM.

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