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Research Articles: Therapeutics, Targets, and Development

Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice

¹ Goldyne Savad Institute of Gene Therapy and ² Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel and ³ Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel

Requests for reprints: Mark Katzenellenbogen, Goldyne Savad Institute of Gene Therapy, Hadassah Medical Organization, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2-6778783; Fax: 972-2-6430982. E-mail: markatz{at}md.huji.ac.il

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. [Mol Cancer Ther 2007;6(4):1283–91]

Grant support: Salzberg Foundation (D. Goldenberg), Kamea Scientific Foundation of the Israeli Government (D. Goldenberg), Blum Foundation (E. Galun), Greenspoon Foundation (E. Galun), Horwitz Foundation (E. Galun), Israeli Science Ministry grant for their support of the Gene Therapy Strategic Center (E. Galun), Horwitz Foundation through The Center for Complexity Science (N. Klopstock and H. Barash), and Jewish National fund grant in memory of Arthur and Ludmila Zuker (N. Klopstock).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: E. Galun holds the Sam and Ellie Fishman Chair in Gene Therapy. E. Domany is the incumbent of the Henry J. Leir Professorial Chair.

⁴ Supplementary materials for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/18/06; revised 11/22/06; accepted 2/ 8/07.