Evaluation of the cytotoxic potential of the UGT8 enzyme inhibitor in glioblastoma cells

• Grant number: 25/01509-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Toxicology
• Principal Investigator: Estela de Oliveira Lima
• Grantee: Hendrew Jesus Barbosa Campos de Souza
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Glioblastoma (GBM) is the most lethal tumor of the Central Nervous System (CNS), with an overall median survival of around 15 months. The efficacy of conventional quarterly treatment is limited by both chemoresistance and the invasive and diffuse nature of the tumor, resulting in frequent relapses. Thus, biomarker-based approaches should be explored in the search for new therapeutic targets. A recent study by the proponent group presented some GBM biomarkers, such as the sulfatide 3-O-Sulfogalactosylceramide. The increase in this molecule, through the metabolization of ceramide via the enzyme Ceramide Galactosyltransferase (UGT8), results in a reduction in the apoptosis of tumor cells induced by ceramide. Previous studies indicate that the inhibition of UGT8 reduces tumor progression, which makes this pathway a relevant target. In addition, a molecule similar to the UGT8 Inhibitor 19 (initially proposed to treat Lysosomal Storage Disorders) reduced galactosylceramide levels in the brains of animal models by 70%, indicating potential for limiting the invasiveness and aggressiveness of GBM. Thus, this work proposes to investigate the cytotoxic potential of UGT8 Inhibitor 19 in in vitro models of temozolomide-resistant GBM spheroids (T98G cells) and to evaluate cell viability using different tests: quantitative MTT test and qualitative Live/Dead test, comparing the results with the analysis of the standard drug - Temozolomide. Once the cytotoxic potential of UGT8 Inhibitor 19 is confirmed in GBM cells resistant to standard chemotherapy, this drug could become a new adjuvant in the treatment of GBM, minimizing the chances of tumor recurrence, reducing additional surgeries and improving patients' quality of life.