Abstract
Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called “hymecromone” where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.
Highlights
There have been an increasing number of studies utilizing 4methylumbelliferone (4-MU) to inhibit hyaluronan (HA) for either experimental or pre-clinical purposes. These studies are notable because of the central role HA plays in many disease processes, including inflammation and cancer progression, and because of the potential utility in repurposing 4-MU, a drug already used in humans for other indications, to treat these diseases
We have reported that low molecular weight-HA (LMW-HA) inhibits the function of Foxp3+ regulatory T-cells (Treg) [38], a cell type that plays a major role in suppressing autoimmunity [55]
(57), we reported that autoimmune insulitis in autoimmune type 1 diabetes (T1D) was associated with isletspecific deposition of HA
Summary
There have been an increasing number of studies utilizing 4methylumbelliferone (4-MU) to inhibit hyaluronan (HA) for either experimental or pre-clinical purposes. These studies are notable because of the central role HA plays in many disease processes, including inflammation and cancer progression, and because of the potential utility in repurposing 4-MU, a drug already used in humans for other indications, to treat these diseases.
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