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Glutathione depletion effect in medulloblastoma chemotherapy

Grant number: 16/09962-8
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2016
Effective date (End): July 31, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Oswaldo Keith Okamoto
Grantee:Beatriz Dias Barbieri
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Medulloblastoma (MB) is the most common form of pediatric brain tumor and it affects the cerebellum. The expression of pluripotency factors, specially of OCT4, has been correlated with poor clinical outcome and resistance to therapy. Chemotherapy resistance is one of the main limiting steps to therapeutic success. Glutathione (GSH), the main antioxidant cellular molecule, exerts a fundamental role in the process of resistance once its mechanism of action results in the efflux of chemotherapeutic agents by the cell. Buthionine sulfoximine (BSO) is an inhibitor of GSH synthesis and its administration is capable of restoring tumor sensitivity to chemotherapy in glioma. However, little is known about the effects of BSO in the treatment of MB, specially in highly tumorigenic cells that exhibit stem cell properties. Therefore, this study aims to investigate whether GSH depletion can enhance the efficacy of chemotherapy against MB. For this reason, we will evaluate the effect of the combined treatment on the viability of highly tumorigenic MB cells, which exhibit stable overexpression of OCT4. Posteriorly, we will analyze the therapeutic efficacy of the combined treatment in vivo through accompaniment of tumor progression in an orthotopic model of MB using immunodeficient mice. This pre-clinical study aims to contribute to the elaboration of novel therapeutic strategies against MB, focusing on alternatives that overcome the acquired tumor resistance to current chemotherapeutic agents. (AU)