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

RODRÍGUEZ MM; MALVICINI M; FIORE E; BUSTILLO SG; PICCIONI F; PEIXOTO E; ATORRASAGASTI C; GARCIA M; ALANIZ L; MAZZOLINI G

Barcelona

Congreso; Reunión anual de la EASL (European Association for the Study of the Liver); 2016

European Association for the Study of the Liver

Background and Aims: The incidence of hepatocellular carcinoma(HCC) has grown significantly in the last decade. Curative treatmentsfor HCC can only be applied in less than 30% of cases. Therefore, newtherapeutic options are needed. We have demonstrated that HCCoverexpressed an essential ECM component, hyaluronic acid (HA)and HA synthesis inhibition using a selective inhibitor 4-methylumbelliferone (4Mu) demonstrated anti-fibrotic andantitumor activity in a murine model of HCC associated with liverfibrosis. The aim of this work was to study the use of 4Mu incombination with gene therapy of interleukin 12 mediated by anadenovirus (AdIL-12) in a murine model of HCC associated withadvanced fibrosis induced by thioacetamide (TAA).Methods: After 4 weeks of TAA administration (200 mg/kg) male C3Hmice received intrahepatic injection of 1,25 × 10e5 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 1 × 10e9 DICT50/mL, i.v (day 9); iv) 4Mu + Adβ-gal 1 ×10e9 DICT50/mL, i.v (day 9); v) 4Mu + AdIL-12 1 × 10e9 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 slightlyreduction of liver tumor volume respect to saline group. Interestingly,combined treatment induced a significant reduction of HCC size (p