TUMOR-SUPPRESSIVE FUNCTIONS OF 4-METHYLUMBELLIFERONE ON HUMAN AML CELLS: STUDY OF HYALURONAN-SYNTHESIS-INHIBITION INDEPENDENT MECHANISMS.

DÍAZ M.; PIBUEL MA; MORENO S; LOMPARDÍA SL; LEDESMA MM; POODTS D.; HAJOS SE; MARCINI T ; EVELSON P; VALACCO P

Virtual

Congreso; Reunión Anual de Sociedades de Biociencias; 2020

SAIC-SAI-SAFIS

Despite continuous improvement in the treatment for acute myeloid leukemia (AML),new therapies are still needed to overcome resistance and reduce adverse effects.We previously proposed that 4-methylumbelliferone (4MU), known as an inhibitor ofhyaluronan (HA) synthesis, would be an interesting new drug for leukemia treatment.Previous results in our lab, showed that 4MU inhibited cell proliferation in a dose-dependent manner in human AML cell lines. Moreover, this drug was able tomodulate mitochondrial status and ROS production. However, it remains to assesswhether the observed effects are explained by the inhibition of HA synthesis. Theaim of this work was to analyze if the anti-tumor activity of 4MU on U937 and THP-1 AML cells could be explained by HA synthesis inhibition. Results showed, that bothAML cell lines were able to produce significant quantities of AH (121.0 ± 0.6 ng/mland 107.6 ± 0.5 ng/ml, respectively) as assessed by ELISA. Surprisingly, 4MU wasable to partially inhibit HA synthesis in THP-1 cells (p< 0.001) but not in U937 cellsat the doses tested. The addition of HA failed to prevent the effects of 4MU onmetabolic activity and cell proliferation in both cell lines, evaluated by XTT and 3H-Tuptake, respectively. Moreover, 4MU+HA co-treatment failed to prevent the increasein the mean of fluorescence of NAO by FC, as well as the increase in ROSproduction, as it was evaluated also by FC with DCF-DA and MitoSox staining, inboth cell lines. These results suggested that there would be 4MU mechanismsindependent of HA synthesis inhibition. To delve further into these mechanisms, weconducted a proteomic study in U937 cells after 4MU treatment by nano LC-MS/MS.Data analysis with free software RStudio resulted in 15 proteins modulated by 4MU(p80), mainly related with cell metabolism signatures, but notdirectly linked to HA synthesis mechanisms. This finding expand the knowledge of4MU for its potential use in AML treatment.