4-methylumbelliferone enhances Temozolomide anti-tumoral effect on glioblastoma cells without affecting normal brain cells.

PIBUEL M; POODTS D; LOMPARDÍA S; DÍAZ M; SILVESTROFF L; HAJOS S; MOLINARI Y; ÁLVAREZ E; FRANCO P

Mar del Plata

Congreso; SAIC.SAI.SAFIS.2018; 2018

SAIC-SAI-SAFIS

Glioblastoma is the most common primary tumor of central nervous system. 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. 4-methylumbelliferone (4MU) is a derivative of coumarins, widely used as a hyaluronan (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, 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), mouse 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, gap closure and metalloproteases activity in a dose dependent manner (p