Combination of 4-methylumbelliferone and adenoviral gene transfer of interleukin-12 reduced the expression of cancer stem cells markers, and showed a potent antitumor effect in an experimental hepatocellular carcinoma model with fibrosis

RODRIGUEZ MARCELO; MALVICINI MARIANA; FIORE ESTEBAN ; GOMEZ BUSTILLO SOFIA; PICCIONI FLAVIA ; PEIXOTO ESTANISLAO ; ATORRASAGASTI, CATALINA; GARCIA, MARIANA; ALANIZ, LAURA; MAZZOLINI, GUILLERMO

Barcelona

Congreso; Liver International Congress; 2016

Background and aims: The incidence of hepatocellular carcinoma (HCC) has grown significantly in the last decade. Curative treatments for HCC can only be applied in less than 30% of cases. Therefore, new therapeutic options are needed. We have demonstrated that HCC overexpressed an essential ECM component, hyaluronic acid (HA) and HA synthesis inhibition using a selective inhibitor 4-methylumbelliferone (4Mu) demonstrated anti-fibrotic and antitumor activity in a murine model of HCC associated with liver fibrosis. The aim of this work was to study the use of 4Mu in combination with gene therapy of interleukin 12 mediated by an adenovirus (AdIL-12) in a murine model of HCC associated with advanced fibrosis induced by thioacetamide (TAA). Methods: After 4 weeks of TAA administration (200mg/kg) male C3H mice received intrahepatic injection of 1,25x10e5 Hepa 129 cells (day 0). On day 5 mice were distributed in experimental groups (n=8/group): i) saline (control); ii) 4Mu 200 mg/Kg, drinking water (day 5); iii) AdIL-12 1x10e9 DICT50/ml , i.v (day 9); iv) 4Mu+ Adβ-gal 1x10e9 DICT50/ml , i.v (day 9); v) 4Mu + AdIL-12 1x10e9 DICT50/ml, i.v. Tumor volume was measured and survival studies were carried out. Tumor samples were taken to determine levels of CSCs. Results: Administration of 4 Mu or AdIL-12 alone induced a slightly reduction of liver tumor volume respect to saline group. Interestingly, combined treatment induced a significant reduction of HCC size (p