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

PICCIONI F; MALVICINI M; GARCIA MG; RODRIGUEZ M; ATORRASAGASTI C; KIPPES N; BUENA IT; RIZZO MM; BAYO J; AQUINO JB; 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