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

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

Cardiff

Conferencia; 2019 HA Conference; 2019

ISHAS

Glioblastoma is the most common primary tumor of the central nervous system (CNS).Migration and invasion are two features strongly associated with high mortality. Aftersurgical resection, radiotherapy and temozolomide treatment, the median survival of patientsis 14 months. Therefore, new drugs are required for glioblastoma therapy. The extracellularmatrix has an important role in tumor progression and development. In the CNS the majorcomponent is the hyaluronic acid (HA) which is involved in several physiological processesbut that in a tumoral context its augment, particularly in GBM, plays an important role inproliferation, migration and invasion of the tumoral cells. 4-methylumbelliferone (4MU) is aderivative of coumarins, widely used as a HA synthesis inhibitor. Recently, some HAindependent effects of 4MU have been reported. Although 4MU anti-tumoral activity wasdescribed on several carcinomas, its effects on glioblastoma were not reported yet. Wehypothesized that 4MU, by independent mechanisms of HA synthesis inhibition, alone or incombination with temozolomide, could inhibit growth and migration of glioblastoma cells,providing a potential therapeutic alternative. The aim of this work was to determine the antitumoral effect of 4MU on glioblastoma cells by evaluating its toxicity and selectivity. Murineglioblastoma cell line (GL26), murine normal brain primary cultures (MNBPC) andGL26/MNBPC co-cultures were used. We evaluated metabolic activity by XTT assay,migration by wound healing assay, metalloproteases activity by zymography and cell deathby FDA/PI and Annexin-V-PE/7AAD using flow cytometry. In GL26 cells, 4MU reducedmetabolic activity, cell migration and metalloproteases activity in a dose-dependent manner(p