4-Methylumbelliferone induces antitumor effects independently of hyaluronan synthesis inhibition in human acute leukemia cell lines

DÍAZ, MARIÁNGELES; PIBUEL, MATÍAS ARTURO; PAGLILLA N.; POODTS, DANIELA; ÁLVAREZ, ÉLIDA; PAPADEMETRIO, DL; HAJOS, SILVIA ELVIRA; LOMPARDÍA, SILVINA LAURA

LIFE SCIENCES

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2021

0024-3205

Aims: Despite continuous improvement in the treatment of acute leukemia, new therapies are stillneeded to overcome resistance and reduce adverse effects. The aim of this work was to study the tumor suppressive effects of 4-methylumbelliferone (4MU) in human acute leukemia cell lines. In addition, we aimed to address the extent of these effects in relation to the inhibition of hyaluronic acid (HA) synthesis.Main methods: HA levels were measured by an ELISA-like assay. Human acute leukemia cell lineswere treated with 4MU, HA or their combination. Cell proliferation was assessed by the [3H]-Tdruptake assay, metabolic activity by the XTT assay and cell death was determined by DAPI, AO/EBand AnnexinV-PE/7-AAD staining. Senescence induction was evaluated by SA-β-Gal and C12FDGstaining. Total and surface RHAMM expression levels were assessed by flow cytometry andfluorescence microscopy.Key findings: 4MU reduced metabolic activity and inhibited cell proliferation in all leukemia cells,and these effects were explained by the induction of senescence or cell death depending on the cellline evaluated. Exogenous HA failed to prevent most of the tumor-suppressive effects observed.Results from this work suggest that the tumor-suppressive effects exerted by 4MU would be explained by HA-synthesis-independent mechanisms.Significance: These findings broaden the knowledge of 4MU as a potential treatment in acuteleukemia. We report for the first time the existence of tumor-suppressive effects of 4MU on humanacute leukemia cell lines that are independent of its role as HA-synthesis inhibitor.