title: Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo.
abstract: Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide. It is intrinsically resistant toward standard chemotherapy, making it imperative to develop novel selective chemotherapeutic agents. The Wnt/beta-catenin pathway plays critical roles in development and oncogenesis, and is dysregulated in HCC. Our study aims to evaluate the activity of 3 small molecule antagonists of the Tcf4/beta-catenin complex (PKF118-310, PKF115-584 and CGP049090) on HCC cell lines in vitro and in vivo. All 3 chemicals displayed dose-dependent cytotoxicity in vitro against all 3 HCC cell lines (HepG2, Hep40 and Huh7), but were at least 10 times less cytotoxic to normal hepatocytes (from 3 donors) by using ATP assay. In HepG2 and Huh7 cells, treatment with the antagonists decreased Tcf4/beta-catenin binding capability and transcriptional activity, associated with downregulation of the endogenous Tcf4/ beta-catenin target genes c-Myc, cyclin D1 and survivin. In HepG2 and Huh7 cells, treatment with the antagonists induced apoptosis and cell cycle arrest at the G1/S phase. All antagonists suppressed in vivo tumor growth in a HepG2 xenograft model, associated with apoptosis and reduced c-Myc, cyclin D1 and survivin expressions. Our results suggest that these 3 antagonists of the Tcf4/beta-catenin complex are potential chemotherapeutic agents which may offer a pathway specific option for the clinical management of HCC.
authors: Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305-5655, USA.
authors: Wei
authors: W
authors: Wei
authors: Mei-Sze
authors: MS
authors: Chua
authors: Susan
authors: S
authors: Grepper
authors: Samuel
authors: S
authors: So
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000187:drug effects; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C538948:CGP049090; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C538949:PKF115-584; C548732:PKF118-310; D011744:Pyrimidinones; D000077022:Survivin; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D014227:Triazines; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D010569:Perylene