BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Nutlin-3 has significant anticancer effects against human HCC cells, regardless of p53 status, indicating that it is a promising therapy for humanhepatocellular carcinoma.
Authors: Alexis Kaushansky; Albert S Ye; Laura S Austin; Sebastian A Mikolajczak; Ashley M Vaughan; Nelly Camargo; Peter G Metzger; Alyse N Douglass; Gavin MacBeath; Stefan H I Kappe Journal: Cell Rep Date: 2013-03-07 Impact factor: 9.423
Authors: R F H Walter; F D Mairinger; S Ting; C Vollbrecht; T Mairinger; D Theegarten; D C Christoph; K W Schmid; J Wohlschlaeger Journal: Br J Cancer Date: 2015-02-10 Impact factor: 7.640
Authors: Zhifeng Gu; Jinxia Jiang; Wei Tan; Yunfei Xia; Haixia Cao; Yan Meng; Zhanyun Da; Hong Liu; Chun Cheng Journal: Clin Dev Immunol Date: 2013-09-16