在包括结肠癌在内的许多类型的人类恶性肿瘤中观察到 Wnt/β-连环蛋白通路的激活失调。废除 Wnt/β-连环蛋白途径已被证明是诱导癌细胞死亡的有效方法。在此，合成了一种新的异恶唑基脲（QR-5）并检查了其对结肠癌细胞系活力的功效。与正常细胞相比，QR-5 对结肠癌细胞表现出选择性细胞毒性。 QR-5 诱导细胞凋亡，亚 G1 细胞升高、Bcl-2、MMP-9、COX-2、VEGF 减少以及 PARP 和 caspase-3 裂解证明了这一点。 QR-5 降低线粒体膜电位，降低 Alix 的表达，升高 ATF4 和 CHOP 的表达，表明诱导了凋亡。凋亡抑制剂 (Z-DEVD-FMK) 和细胞凋亡抑制剂 (CHX) 不能恢复 QR-5 处理的细胞中的 Alix 表达和 PARP 裂解，分别表明两种细胞死亡途径之间的互补。 QR-5 抑制 Wnt/β-连环蛋白途径蛋白的表达，核和细胞质 β-连环蛋白的下调也证明了这一点。使用 β-连环蛋白特异性 siRNA 进行敲除实验，证明了 QR-5 对 β-连环蛋白诱导细胞凋亡和近凋亡的依赖性。总体而言，QR-5 通过减轻结肠癌细胞中的 Wnt/β-连环蛋白轴来诱导细胞凋亡和近凋亡。版权所有 © 2024。由 Elsevier B.V. 出版。

Deregulated activation of the Wnt/β-catenin pathway is observed in many types of human malignancies including colon cancer. Abrogation of the Wnt/β-catenin pathway has been demonstrated as an effective way of inducing cancer cell death. Herein, a new isoxazolyl-urea (QR-5) was synthesized and examined its efficacy on the viability of colon cancer cell lines. QR-5 displayed selective cytotoxicity towards colon cancer cells over normal counterparts. QR-5 induced apoptosis as evidenced by elevation in sub-G1 cells, decrease in Bcl-2, MMP-9, COX-2, VEGF and cleavage of PARP and caspase-3. QR-5 reduced the mitochondrial membrane potential, decreased the expression of Alix and elevated the expression of ATF4 and CHOP indicating the induction of paraptosis. The inhibitor of apoptosis (Z-DEVD-FMK) and paraptosis (CHX) could not restore Alix expression and PARP cleavage in QR-5 treated cells, respectively suggesting the complementation between the two cell death pathways. QR-5 suppressed the expression of Wnt/β-catenin pathway proteins which was also evidenced by the downregulation of nuclear and cytoplasmic β-catenin. The dependency of QR-5 on β-catenin for inducing apoptosis and paraptosis was demonstrated using knockdown experiments using β-catenin specific siRNA. Overall, QR-5 induces apoptosis as well as paraptosis by mitigating the Wnt/β-catenin axis in colon cancer cells.Copyright © 2024. Published by Elsevier B.V.