MDM2 antagonist can inhibit tumor growth in hepatocellular carcinoma with different types of p53 in vitro.
Nutlin-3, a selective small-molecule inhibitor of the p53-MDM2 interaction, has been shown to have antitumor activities in various tumors with wild-type p53. However, its effect on hepatocellular carcinoma (HCC) with different types of p53 remains unclear. This study is designed to determine nutlin-3's antitumor efficacy and underlying mechanisms of action ... in human HCC cells.Cell viability assay, cell cycle analysis, apoptosis assay, western blot, co- immunoprecipitation and siRNA experiments were analyzed in three human HCC cells. Anti-tumoral effects of nutlin-3 targeting the p53 and p73 pathways were evaluated in HCC cell lines.Nutlin-3 exerted the greatest anti-tumoral effect to three human HCC cells with wild-type p53, mutant p53 and p53-null. Nutlin-3 not only upregulated p53 in HepG2 cells, but also p73 in Huh7 and Hep3B cells, and disrupted p53-MDM2 and p73-MDM2 complexes in HCC cells. The compound inhibited cell proliferation, induced G0/G1 phase arrest, decreased the levels of CyclinD1, CyclinE, CDK2, CDK4, PCNA and E2F-1, and increased the levels of p21 and p27. It also induced apoptosis, increased the Bax/Bcl-2 ratio, then activated caspase-9 and caspase-3.Nutlin-3 has significant anticancer effects against human HCC cells, regardless of p53 status, indicating that it is a promising therapy for human hepatocellular carcinoma.
Mesh Terms:
Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Western, Carcinoma, Hepatocellular, Cell Cycle, Cell Cycle Proteins, Cell Proliferation, Cell Survival, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme Inhibitors, Flow Cytometry, Hep G2 Cells, Humans, Imidazoles, Immunoprecipitation, Liver Neoplasms, Mutation, Nuclear Proteins, Piperazines, Proto-Oncogene Proteins c-mdm2, RNA Interference, Time Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Western, Carcinoma, Hepatocellular, Cell Cycle, Cell Cycle Proteins, Cell Proliferation, Cell Survival, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme Inhibitors, Flow Cytometry, Hep G2 Cells, Humans, Imidazoles, Immunoprecipitation, Liver Neoplasms, Mutation, Nuclear Proteins, Piperazines, Proto-Oncogene Proteins c-mdm2, RNA Interference, Time Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
J. Gastroenterol. Hepatol.
Date: Feb. 01, 2011
PubMed ID: 21261729
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