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
J. Gastroenterol. Hepatol.
Date: Feb. 01, 2011
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