Wnt/β-catenin signaling inhibitors.
Wnt/β-catenin signaling inhibitors.
复制标题
Wnt/β-连环蛋白信号传导抑制剂。
DOI：
10.2174/1568026623666230303101810
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发表时间：
2023
影响因子：
3.4
通讯作者：
Nazhen Dong
中科院分区：
文献类型：
--
作者：
Xiaoyan Hu;Xun Zhang;Nazhen Dong
Wnt/β-连环蛋白信号通路在癌症的发生、组织稳态、血管生成和癌变中发挥着至关重要的作用。癌细胞和癌症干细胞中Wnt/β-catenin信号通路的突变和过度激活导致接受常规化疗和放疗的患者产生耐药性和癌症复发。肿瘤血管生成过程中，过度激活的 Wnt/β-连环蛋白信号持续诱导促血管生成因子上调。此外，突变和过度激活的 Wnt/β-连环蛋白信号传导与多种人类癌症（包括乳腺癌、宫颈癌和神经胶质瘤）的较差结果相关。因此，Wnt/β-连环蛋白信号的突变和过度激活给癌症治疗带来了挑战和限制。最近，计算机药物设计以及高通量分析和实验证明了化疗药物具有良好的抗癌功效，例如阻断癌细胞周期、抑制癌细胞增殖和内皮细胞血管生成、诱导癌细胞凋亡、去除癌症干细胞和增强免疫反应。与传统的化疗和放疗相比，小分子抑制剂被认为是针对Wnt/β-catenin信号通路最有前途的治疗策略。本文综述了目前Wnt/β-catenin信号通路的小分子抑制剂，重点关注Wnt配体、Wnt受体、β-catenin破坏复合物、泛素连接酶和蛋白酶体破坏复合物、β-catenin、β-catenin相关转录因子和共激活因子以及促血管生成因子。我们在临床前和临床试验中描述了这些小分子在癌症治疗过程中的结构、机制和功能。我们还回顾了几种据报道具有抗血管生成作用的 Wnt/β-连环蛋白抑制剂。最后，我们解释了人类癌症治疗中 Wnt/β-catenin 信号通路靶向的各种挑战，并提出了人类癌症的潜在治疗方法。
The Wnt/β-catenin signaling pathway plays a crucial role in the development, tissue homeostasis, angiogenesis, and carcinogenesis of cancer. Mutations and excessive activation of the Wnt/β-catenin signaling pathway in cancer cells and cancer stem cells lead to drug resistance and recurrence of cancer in patients treated with conventional chemotherapy and radiotherapy. Upregulation of proangiogenic factors is persistently induced by hyperactivated Wnt/β-catenin signaling during tumor angiogenesis. Furthermore, mutations and hyperactivated Wnt/β-catenin signaling are associated with worse outcomes in several human cancers, including breast cancer, cervical cancer, and glioma. Therefore, mutations and hyperactivation of Wnt/β-catenin signaling create challenges and limitations in cancer treatment. Recently, in silico drug design as well as high-throughput assays and experiments have demonstrated the promising anticancer efficacy of chemotherapeutics, such as blocking the cancer cell cycle, inhibiting cancer cell proliferation and endothelial cell angiogenesis, inducing cancer cell apoptosis, removing cancer stem cells, and enhancing immune responses. Compared to conventional chemotherapy and radiotherapy, small-molecule inhibitors are considered the most promising therapeutic strategy for targeting the Wnt/β-catenin signaling pathway. Herein, we review the current small-molecule inhibitors of the Wnt/β-catenin signaling pathway, focusing on Wnt ligands, Wnt receptors, the β-catenin destruction complex, ubiquitin ligase and proteasomal destruction complex, β-catenin, β-catenin-associated transcriptional factors and co-activators, and proangiogenic factors. We describe the structure, mechanisms, and functions of these small molecules during cancer treatment in preclinical and clinical trials. We also review several Wnt/β-catenin inhibitors reported to exhibit anti-angiogenic effects. Finally, we explain various challenges in the targeting of the Wnt/β-catenin signaling pathway in human cancer treatment and suggest potential therapeutic approaches to human cancer.