Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
J Gastroenterol Hepatol. 2011 Feb;26(2):371-7. doi: 10.1111/j.1440-1746.2010.06440.x.
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.
Nutlin-3 是一种 p53-MDM2 相互作用的选择性小分子抑制剂，已被证明在具有野生型 p53 的各种肿瘤中具有抗肿瘤活性。然而，其对具有不同 p53 类型的肝细胞癌（HCC）的影响尚不清楚。本研究旨在确定 Nutlin-3 在人 HCC 细胞中的抗肿瘤功效和作用机制。
在三种人 HCC 细胞中分析细胞活力测定、细胞周期分析、凋亡测定、western blot、共免疫沉淀和 siRNA 实验。评估 Nutlin-3 针对 p53 和 p73 通路对 HCC 细胞系的抗肿瘤作用。
Nutlin-3 对三种具有野生型 p53、突变型 p53 和 p53 缺失的人 HCC 细胞表现出最大的抗肿瘤作用。Nutlin-3 不仅上调了 HepG2 细胞中的 p53，还上调了 Huh7 和 Hep3B 细胞中的 p73，并破坏了 HCC 细胞中的 p53-MDM2 和 p73-MDM2 复合物。该化合物抑制细胞增殖，诱导 G0/G1 期阻滞，降低细胞周期蛋白 D1、E、CDK2、CDK4、PCNA 和 E2F-1 的水平，增加 p21 和 p27 的水平。它还诱导细胞凋亡，增加 Bax/Bcl-2 比值，然后激活 caspase-9 和 caspase-3。
Nutlin-3 对人 HCC 细胞具有显著的抗癌作用，无论 p53 状态如何，表明它是治疗人肝细胞癌的一种有前途的疗法。
