title: Selective poisoning of Ctnnb1-mutated hepatoma cells in mouse liver tumors by a single application of acetaminophen.
abstract: Mouse liver tumors that harbor activating mutations in Ctnnb1, encoding β-catenin, express high levels of various cytochromes P450 (CYP), including CYP2E1 and CYP1A2. Acetaminophen (AAP) is metabolized in hepatocytes by these CYPs to the reactive intermediate N-acetyl-p-benzoquinone-imine, which is toxic to hepatocytes at high doses where depletion of glutathione occurs. We have induced liver tumors in mice by treatment with the liver carcinogen N-nitrosodiethylamine followed by chronic treatment with the tumor promoter phenobarbital. Under this protocol, ~80 % of tumors display Ctnnb1 mutations and express high levels of various CYP isoforms. Tumor-bearing animals were given a single intraperitoneal injection of 300 mg/kg body weight AAP, which was well tolerated by the animals. This dose, however, eradicated essentially all larger Ctnnb1-mutated, CYP-positive liver tumors, killing >90 % of hepatoma cells: at 2 days after AAP, large necrotic areas filled with cell debris were observed in tumors. These were infiltrated in the following days by immune cells starting from the outer parts of the damaged areas slowly closing the "wounds" left from the poisoned tumor cells. During this period, there was increased proliferation of normal hepatocytes, but some residual tumor cells were also proliferating. Our results show that a selective poisoning of Ctnnb1-mutated liver tumors by administration of AAP is possible in this experimental system. Application of an adapted protocol could be envisaged for neo-adjuvant treatment of human hepatoblastoma which are frequently mutated in CTNNB1 and often show high expression of CYP2E1.
authors.affiliation: Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tuebingen, Wilhelmstr. 56, 72074, Tübingen, Germany.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Singh
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmid
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010634:Phenobarbital / Q000633:toxicity; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D051176:beta Catenin; D000082:Acetaminophen; D004052:Diethylnitrosamine; D019392:Cytochrome P-450 CYP2E1; D010634:Phenobarbital