info:eu-repo/semantics/article
Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice
Registro en:
Piccioni, Flavia Valeria; Malvicini, Mariana; García, Mariana Gabriela; Rodriguez, Andrés; Atorrasagasti, María Catalina; et al.; Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice; Oxford Univ Press Inc; Glycobiology; 22; 3; 3-2012; 400-410
0959-6658
CONICET Digital
CONICET
Autor
Piccioni, Flavia Valeria
Malvicini, Mariana
García, Mariana Gabriela
Rodriguez, Andrés
Atorrasagasti, María Catalina
Kippes, Néstor Fabián
Piedra Buena, Ignacio T.
Rizzo, Manglio Miguel
Bayo Fina, Juan Miguel
Aquino, Jorge Benjamin
Viola, Manuela
Passi, Alberto
Alaniz, Laura Daniela
Mazzolini Rizzo, Guillermo Daniel
Resumen
Liver cirrhosis is characterized by an excessive accumulation of extracellular matrix components, including hyaluronan (HA). In addition, cirrhosis is considered a pre-neoplastic disease for hepatocellular carcinoma (HCC). Altered HA biosynthesis is associated with cancer progression but its role in HCC is unknown. 4-Methylumbelliferone (4-MU), an orally available agent, is an HA synthesis inhibitor with anticancer properties. In this work, we used an orthotopic Hepa129 HCC model established in fibrotic livers induced by thioacetamide. We evaluated 4-MU effects on HCC cells and hepatic stellate cells (HSCs) in vitro by proliferation, apoptosis and cytotoxicity assays; tumor growth and fibrogenesis were also analyzed in vivo. Our results showed that treatment of HCC cells with 4-MU significantly reduced tumor cell proliferation and induced apoptosis, while primary cultured hepatocytes remained unaffected. 4-MU therapy reduced hepatic and systemic levels of HA. Tumors systemically treated with 4-MU showed the extensive areas of necrosis, inflammatory infiltrate and 2-3-fold reduced number of tumor satellites. No signs of toxicity were observed after 4-MU therapy. Animals treated with 4-MU developed a reduced fibrosis degree compared with controls (F1-2 vs F2-3, respectively). Importantly, 4-MU induced the apoptosis of HSCs in vitro and decreased the amount of activated HSCs in vivo. In conclusion, our results suggest a role for 4-MU as an anticancer agent for HCC associated with advanced fibrosis. Fil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina Fil: Malvicini, Mariana. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: García, Mariana Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina Fil: Rodriguez, Andrés. Universidad Austral; Argentina Fil: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad Austral; Argentina Fil: Kippes, Néstor Fabián. Universidad Austral; Argentina Fil: Piedra Buena, Ignacio T.. Universidad Austral; Argentina Fil: Rizzo, Manglio Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina Fil: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina. Ministerio de Ciencia. Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica; Argentina Fil: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina Fil: Viola, Manuela. Universitá degli Studi dell’Insubria; Italia Fil: Passi, Alberto. Universitá degli Studi dell’Insubria; Italia Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentina