4-Methylumbelliferone as a potent and selective antitumor drug on a glioblastoma model

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

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Lugar: Oxford; Año: 2020 vol. 9 p. 29 - 43

0959-6658

Glioblastoma (GBM), the most frequent primary tumor of the central nervous system, has a mediansurvival of 14.6 months. 4-Methylumbelliferone (4MU) is a coumarin derivative widely used as ahyaluronan synthesis inhibitor with proven antitumor activity and without toxic effects reported.We aim to evaluate the antitumor effect of 4MU alone or combined with temozolomide (TMZ)on a GBM cell line, its absence of toxicity on brain cells and its selectivity for tumor cells. Theantitumor effect of 4MU alone or combined with TMZ was evaluated on GL26 cells by assessing themetabolic activity through the XTT assay, cell proliferation by BrdU incorporation assay, migrationby the wound healing assay, cell death by fluorescein diacetate/propidium iodide (FDA/PI) staining,apoptosis by membrane asymmetry and DNA fragmentation and metalloproteinase activity byzymography. The levels of hyaluronan and its capacity to counteract the effects of 4MU and theexpression of RHAMM and CD44 were also determined. The toxicity and selectivity of 4MU weredetermined by XTT assay and PI staining on normal brain primary cell culture (NBPC-GFP) andGL26/NBPC-GFP cocultures. The GL26 cells expressed RHAMM but not CD44 while synthetizedhyaluronan. 4MU decreased hyaluronan synthesis, diminished proliferation and induced apoptosiswhile reducing cell migration and the activity of metalloproteinases, which was restored by additionof hyaluronic acid. Furthermore, 4MU sensitized GL26 cells to the TMZ effect and showed selectivetoxicity on tumor cells without exhibiting neurotoxic effects. We demonstrated for the first timethe cytotoxic effect of 4MU on GBM cells, highlighting its potential usefulness to improve GBM treatment.