A hyaluronic acid biosynthesis inhibitor: 4-Methylumbelliferone

Introduction

4-Methylumbelliferone (4MU) is a hyaluronic acid biosynthesis inhibitor with antitumoral and antimetastatic effects[1]. 4MU is a natural coumarin derivative without adverse effects reported that is commercially available as “hymecromone”, as it is used in Europe and Asia as a choleretic and antispasmodic drug for treating biliary spasm. Its effects on other pathologies, such as autoimmune diseases, cancer, and COVID-19,, are being explored.

Property

4MU is umbelliferone methylated at position four. It has the IUPAC name 7-hydroxy-4-methylcoumarin and the international free name (INN) hymecromone. It has the molecular formula C10H8O3, a molecular weight of 176.2 kDa, a CAS number of 90-33-5, and a pKa of 7.79. The melting point of 4MU is 194–195°C. 4MU is soluble in methanol with heating, DMSO, and glacial acetic acid. It is slightly soluble in ether or chloroform and practically insoluble in water. 4MU is known for its fluorescent properties and has an excitation wavelength of 380 nm and an emission wavelength of 454 nm in water. It is colourless at pH 7.0 and exhibits a blue fluorescence at pH 7.5. In light of these properties, it has been used extensively as a pH-sensitive fluorescent indicator in multiple experimental settings[2].

Uses

4MU is a known hyaluronan (HA) synthesis inhibitor, via the inhibition of HA synthases expression and depletion of their substrate, UDP-glucuronic acid. It was recently demonstrated that oral administration of 4MU in healthy patients diminished HA content in serum and sputum, showing that its effect on HA metabolism is systemically relevant. Lately, our and other groups have shown that 4MU exerts some of its effects in an HA-independent manner, highlighting its potential as an alternative therapy. In this way, 4MU diminishes cell proliferation and migration and induces antitumor mechanisms, such as apoptosis and senescence, in a wide variety of cancer types, including ovarian, breast, hepatocellular, pancreatic, prostate, fibrosarcoma, chronic and acute myeloid leukemia, osteosarcoma, malignant pleural mesothelioma, among others. Research determined the antitumor effects of 4MU on a murine and two human GBM cell lines, mainly consisting of inhibition of cell proliferation, induction of apoptosis in the murine model, and induction of senescence and migration in the human model. Furthermore, a recent publication showed the efficacy of 4MU in an in vivo Glioblastoma model[3].

Biological activity

4MU is a new inhibitor of both in vitro and in vivo angiogenesis. In vitro, 4MU affects several critical steps of angiogenesis, including endothelial cell proliferation, adhesion, tube formation, and extracellular matrix remodelling. Half-maximal inhibitory concentrations (IC50) values in the proliferation assay were 0.65 ± 0.04 and 0.37 ± 0.03 mM for HMEC and RF-24 endothelial cells, respectively. 4MU (2 mM) treatment for 24 h induced apoptosis in 13% of HMEC and 5% of RF-24 cells. The number of adherent endothelial cells decreased by >20% after 24 h of treatment with 1 mM 4MU. Minimal inhibitory concentrations in the tube formation assay were 2 and 0.5 mM 4MU for HMEC and RF-24, respectively. Matrix metalloproteinase-2 expression was differentially altered upon 4MU treatment in both tested endothelial cell lines. The results suggest that 4MU may have potential as a new candidate multitargeted bioactive compound for antiangiogenic therapy.

[1] Javier A. García-Vilas, Miguel Ángel Medina*, Ana R. Quesada. “4-Methylumbelliferone Inhibits Angiogenesis in Vitro and in Vivo.” Journal of Agricultural and Food Chemistry 61 17 (2013): 4063–4071.

[2] Nadine Nagy. “4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer.” Frontiers in Immunology (2015): 123.

[3] Matías A Pibuel. “4-Methylumbelliferone enhances the effects of chemotherapy on both temozolomide-sensitive and resistant glioblastoma cells.” Scientific Reports 13 1 (2023): 9356.

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