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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / drug effects
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Cell Line, Tumor
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Cyclin D1 / drug effects
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, myc / drug effects
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Immunohistochemistry
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Inhibitor of Apoptosis Proteins
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Mice
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Mice, Nude
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Microtubule-Associated Proteins / drug effects
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Perylene / analogs & derivatives
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Perylene / pharmacology
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Pyrimidinones / pharmacology
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Random Allocation
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Signal Transduction / drug effects
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Survivin
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Transcription Factor 4
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Transcription Factors / drug effects
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Transcription Factors / metabolism*
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Triazines / pharmacology
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Wnt Proteins / metabolism
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Xenograft Model Antitumor Assays
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beta Catenin / drug effects
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beta Catenin / metabolism*
Substances
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Antineoplastic Agents
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BIRC5 protein, human
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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CGP049090
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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PKF115-584
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PKF118-310
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Pyrimidinones
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Survivin
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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Triazines
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Wnt Proteins
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beta Catenin
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Cyclin D1
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Perylene