Small molecule antagonists of Tcf4/β-catenin complex inhibit the growth of HCC cells in vitro and in vivo
Small molecule antagonists of Tcf4/β-catenin complex inhibit the growth of HCC cells in vitro and in vivo
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DOI：
10.1002/ijc.24810
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发表时间：
2010-05-15
影响因子：
6.4
通讯作者：
So, Samuel
中科院分区：
文献类型：
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作者：
Wei, Wei;Chua, Mei-Sze;So, Samuel
肝细胞癌 (HCC) 是全球第五大常见癌症。它对标准化疗有本质上的抵抗力，因此开发新型选择性化疗药物势在必行。 Wnt/β-连环蛋白通路在发育和肿瘤发生中发挥着关键作用，并且在 HCC 中失调。我们的研究旨在评估 Tcf4/β-连环蛋白复合物的 3 种小分子拮抗剂（PKF118-310、PKF115-584 和 CGP049090）在体外和体内对 HCC 细胞系的活性。所有 3 种化学品在体外对所有 3 种 HCC 细胞系（HepG2、Hep40 和 Huh7）均表现出剂量依赖性细胞毒性，但通过 ATP 测定，对正常肝细胞（来自 3 个供体）的细胞毒性至少低 10 倍。在 HepG2 和 Huh7 细胞中，拮抗剂处理降低了 Tcf4/β-catenin 结合能力和转录活性，与内源性 Tc14/β-catenin 靶基因 c-Myc、cyclin D1 和 survivin 的下调相关。在 HepG2 和 Huh7 细胞中，拮抗剂处理诱导细胞凋亡和细胞周期停滞在 G1/S 期。所有拮抗剂均抑制 HepG2 异种移植模型中的体内肿瘤生长，与细胞凋亡和 c-Myc、细胞周期蛋白 D1 和存活蛋白表达减少相关。我们的结果表明，Tcf4/β-连环蛋白复合物的这 3 种拮抗剂是潜在的化疗药物，可能为 HCC 的临床治疗提供途径特异性选择。
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 Tc14/ 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.