Antitumor effects of hyaluronic acid inhibitor 4-Methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice.

PICCIONI F, MALVICINI M, GARCIA MG, RODRIGUEZ A, ATORRASAGASTI C, KIPPES N, BUENA IT, RIZZO MM, BAYO J, AQUINO J, VIOLA M, PASSI A, ALANIZ L, MAZZOLINI G.

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Año: 2011

0959-6658

Liver cirrhosis is characterized by an excessive accumulation of extracellular matrix components, including hyaluronan. In addition, cirrhosis is considered a pre-neoplastic disease for hepatocellular carcinoma. Altered hyaluronan biosynthesis is associated with cancer progression but its role in hepatocellular carcinoma is unknown. 4-methylumbelliferone, an orally available agent, is a hyaluronan synthesis inhibitor with anticancer properties. In this work we used an orthotopic Hepa129 hepatocellular carcinoma model established in fibrotic livers induced by thioacetamide. We evaluated 4-methylumbelliferone effects on hepatocellular carcinoma cells and hepatic stellate cells in vitro by proliferation, apoptosis and cytotoxicity assays; tumor growth and fibrogenesis were also analyzed in vivo. Our results showed that treatment of hepatocellular carcinoma cells with 4-methylumbelliferone significantly reduced tumor cell proliferation and induced apoptosis, while primary cultured hepatocytes remained unaffected. 4-methylumbelliferone therapy reduced hepatic and systemic levels of hyaluronan. Tumors systemically treated with 4-methylumbelliferone showed extensive areas of necrosis, inflammatory infiltrate and 2-3-folds reduced number of tumor satellites. No signs of toxicity were observed after 4-methylumbelliferone therapy. Animals treated with 4-methylumbelliferone developed a reduced fibrosis degree compared with controls (F1-2 vs F2-3, respectively). Importantly, 4-methylumbelliferone induced apoptosis of hepatic stellate cells in vitro and decreased the amount of activated hepatic stellate cells in vivo. In conclusion, our results suggest a role for 4-methylumbelliferone as anticancer agent for hepatocellular carcinoma associated to advanced fibrosis.