Abstract 5447: Enhanced antitumoral effect of the glycosylated 4-methylumbelliferone in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, and is particularly refractory to the available therapeutic drugs. Unfortunately, curative treatments such as surgery, liver transplantation, or ablation are reserved for early stages and can only be applied in less than 30% of the patients with HCC. Glycosylation can be a potent and interesting strategy for drug delivery to a specific target. We enzymatically synthesized a glycosylated derivative of the coumarin 4-methylumbelliferone (4MU), namely 4MUR.The antitumoral effect of 4MUR in comparison with the aglycone 4MU was evaluated onto liver cancer cells. Cellular toxicity was determined on murine liver tumor cell lines as well as non-hepatic tumoral cells. Tumor cell lines were significantly more sensitive than non-tumoral cells to the glycosylated molecule in a dose-dependent manner (p<0.05). 4MUR was incorporated mostly into tumoral cells by the interaction with the asialoglycoprotein receptor (ASGPR), which is overexpressed in liver tumor cells. Hyaluronic acid (HA) is the major component of the extracellular matrix (ECM). It is produced at the plasma membrane by three hyaluronan synthases (HAS1, 2 and 3), which couple glucuronic acid and N-acetylglucosamine into a linear polymer using the corresponding UDP-sugars (UDP-GlcUA and UDP-GlcNAc) as substrates. Unlike 4MUR, the glucuronidation of 4MU competitively inhibits chain elongation of HA. Furthermore, 4MUR treatment regulates the levels of HAS2 and HAS3 expression in the tumoral cell line. Finally, 4MUR treatment induced apoptosis cell death in tumoral cells. Our results suggest that the 4MUR is safe and effective against liver tumor cells via a specific targeting to ASGPR receptor and decreasing HA synthesis. Citation Format: Gisela Weiz, Alina L. Gonzalez, Flavia Piccioni, Mariel Fusco, Marco Diaz Gutiérrez, Guillermo Mazzolini, Javier D. Breccia, Mariana Malvicini, Maria I. Molejon. Enhanced antitumoral effect of the glycosylated 4-methylumbelliferone in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5447.