Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
Center for Instrumental Analysis, Kyoto Pharmaceutical University, Kyoto, Japan.
Biochem Biophys Res Commun. 2021 Jan 8;535:73-79. doi: 10.1016/j.bbrc.2020.12.027. Epub 2020 Dec 18.
The Wnt/β-catenin pathway is an attractive target for the treatment of acute myelogenous leukemia (AML), since aberrant activation of the Wnt/β-catenin pathway contributes to carcinogenesis in various types of cancers including AML. Screening of an in-house compound library, constructed at Kyoto Pharmaceutical University, identified a novel compound designated "31" that was found to be an inhibitor of the Wnt/β-catenin pathway. The compound inhibited T-cell factor (TCF) activity in a TCF firefly luciferase-reporter assay and suppressed the proliferation of several human AML cell lines in a dose-dependent manner. Compound 31 arrested the cell cycle of AML cells at the G1 stage and induced apoptosis. Decrease in protein and mRNA expression level of Wnt pathway-related molecules was confirmed by the analyses of western blotting and quantitative reverse transcription-polymerase chain reaction. In addition, compound 31 combined with idarubicin synergistically inhibited the proliferation of AML cells. In conclusion, these results strongly suggest that compound 31 has potential as a novel anti-AML agent targeting the Wnt/β-catenin signaling pathway.
Wnt/β-连环蛋白通路是治疗急性髓细胞性白血病（AML）的一个有吸引力的靶点，因为该通路的异常激活导致包括 AML 在内的多种癌症的发生。在京都药科大学构建的内部化合物库中进行筛选，鉴定出一种新型化合物，命名为“31”，它被发现是 Wnt/β-连环蛋白通路的抑制剂。该化合物在 T 细胞因子（TCF）萤火虫荧光素酶报告基因测定中抑制 TCF 活性，并以剂量依赖性方式抑制几种人 AML 细胞系的增殖。化合物 31 将 AML 细胞的细胞周期阻滞在 G1 期，并诱导细胞凋亡。通过 Western blot 和定量逆转录聚合酶链反应分析证实了 Wnt 通路相关分子的蛋白和 mRNA 表达水平降低。此外，化合物 31 与伊达比星联合使用可协同抑制 AML 细胞的增殖。总之，这些结果强烈表明，化合物 31 具有作为一种针对 Wnt/β-连环蛋白信号通路的新型抗 AML 药物的潜力。
