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

DIAZ MARIANGELES; PIBUEL MATÍAS; PAGLILLA NADIA; POODTS, DANIELA; ALVAREZ ELIDA; PAPADEMETRIO DANIELA; HAJOS SILVIA; LOMPARDÍA SILVINA

LIFE SCIENCES

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2021 vol. 287 p. 1 - 12

0024-3205

Aims: Despite continuous improvement in the treatment of acute leukemia, new therapies are still needed toovercome resistance and reduce adverse effects. The aim of this work was to study the tumor-suppressive effectsof 4-methylumbelliferone (4MU) in human acute leukemia cell lines. In addition, we aimed to address the extentof 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 lines were treatedwith 4MU, HA or their combination. Cell proliferation was assessed by the [3H]-Tdr uptake assay, metabolicactivity by the XTT assay and cell death was determined by DAPI, AO/EB and AnnexinV-PE/7-AAD staining.Senescence induction was evaluated by SA-β-Gal and C12FDG staining. Total and surface RHAMM expressionlevels were assessed by flow cytometry and fluorescence microscopy.Key findings: 4MU reduced metabolic activity and inhibited cell proliferation in all leukemia cells, and theseeffects were explained by the induction of senescence or cell death depending on the cell line evaluated.Exogenous HA failed to prevent most of the tumor-suppressive effects observed. Results from this work suggestthat the tumor-suppressive effects exerted by 4MU would be explained by HA-synthesis-independentmechanisms.Significance: These findings broaden the knowledge of 4MU as a potential treatment in acute leukemia. We reportfor the first time the existence of tumor-suppressive effects of 4MU on human acute leukemia cell lines that areindependent of its role as HA-synthesis inhibitor.