title: Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice.
abstract: Dietary antioxidants and selenium compounds were shown to have a therapeutic effect against hepatocellular carcinoma in several mouse models. We tested the effects of tannic acid and selenomethionine on hepatocellular carcinoma development in Mdr2 knockout (Mdr2-KO) mice. Mdr2-KO and age-matched Mdr2 heterozygous control mice were fed with tannic acid or selenomethionine during the first 3 months of life. Then, several mice from each group were sacrificed, and liver tissue samples were removed for analysis. The remaining mice were fed a regular diet until the age of 16 months, at which time the number and size of liver tumors were determined. Liver tissue samples of 3-month-old mice were subjected to gene expression profiling analysis using cDNA macroarrays containing probes for 240 genes that regulate responses to oxidative stress and inflammation or lipid metabolism. Both tannic acid and selenomethionine had partial chemopreventive effect on development of hepatocellular carcinoma in Mdr2-KO mice: they reduced the incidence of large tumor nodules (diameter >1 cm) at age 16 months. Both agents inhibited gene expression and reversed up-regulation of many genes that control inflammation or response to oxidative stress in Mdr2-KO livers at age 3 months. This inhibitory effect on gene expression correlated with the ability of agents to reduce incidence of large tumors: selenomethionine was more active than tannic acid in both aspects. Understanding the molecular mechanism of chemoprevention effect could improve our therapeutic modalities while using these agents.
authors: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. markatz@md.huji.ac.il
authors: Mark
authors: M
authors: Katzenellenbogen
authors: Lina
authors: L
authors: Mizrahi
authors: Orit
authors: O
authors: Pappo
authors: Naama
authors: N
authors: Klopstock
authors: Devorah
authors: D
authors: Olam
authors: Hila
authors: H
authors: Barash
authors: Eytan
authors: E
authors: Domany
authors: Eithan
authors: E
authors: Galun
authors: Daniel
authors: D
authors: Goldenberg
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D018890:Chemoprevention; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012645:Selenomethionine / Q000494:pharmacology* / Q000627:therapeutic use; D013634:Tannins / Q000494:pharmacology* / Q000627:therapeutic use; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018809:Proliferating Cell Nuclear Antigen; D012645:Selenomethionine; D013634:Tannins; D000097202:ATP-Binding Cassette Sub-Family B Member 4