4-methylumbelliferone would act by independent mechanisms of the synthesis inhibition of Hialuronic acid, and enhances Temozolomide anti-tumoral effect on glioblastoma cells without affecting normal brain cells.

PIBUEL MATÍAS; POODTS DANIELA; FRANCO PAULA; DÍAZ MARIÁNGELES; LOMPARDÍA SILVINA; MOLINARI YAMILA; SILVESTROFF LUCAS; HAJOS SILVIA E.

Cardiff

Congreso; Hyaluronan Meeting 2019; 2019

Glioblastoma is the most common primary tumor of the central nervous system (CNS). Migration and invasion are two features strongly associated with high mortality. After surgical resection, radiotherapy and temozolomide treatment, the median survival of patients is 14 months. Therefore, new drugs are required for glioblastoma therapy. The extracellular matrix has an important role in tumor progression and development. In the CNS the major component is the hyaluronic acid (HA) which is involved in several physiological processes but that in a tumoral context its augment, particularly in GBM, plays an important role in proliferation, migration and invasion of the tumoral cells. 4-methylumbelliferone (4MU) is a derivative of coumarins, widely used as a HA synthesis inhibitor. Recently, some HA-independent effects of 4MU have been reported. Although 4MU anti-tumoral activity was described on several carcinomas, its effects on glioblastoma were not reported yet. We hypothesized that 4MU, by independent mechanisms of HA synthesis inhibition, alone or in combination with temozolomide, could inhibit growth and migration of glioblastoma cells, providing a potential therapeutic alternative. The aim of this work was to determine the anti-tumoral effect of 4MU on glioblastoma cells by evaluating its toxicity and selectivity. Murine glioblastoma cell line (GL26), murine normal brain primary cultures (MNBPC) and GL26/MNBPC co-cultures were used. We evaluated metabolic activity by XTT assay, migration by wound healing assay, metalloproteases activity by zymography and cell death by FDA/PI and Annexin-V-PE/7AAD using flow cytometry. In GL26 cells, 4MU reduced metabolic activity, cell migration and metalloproteases activity in a dose-dependent manner (p