Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
Department of Clinical Laboratory, Tianjin Beichen Hospital, Tianjin, 300400, China.
Curr Top Med Chem. 2023;23(10):880-896. doi: 10.2174/1568026623666230303101810.
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 ligases and proteasomal destruction complex, β-catenin, β-catenin-associated transcriptional factors and coactivators, 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.
Wnt/β-catenin 信号通路在癌症的发生发展、组织稳态、血管生成和癌变中起着至关重要的作用。癌症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的癌症耐药和复发。在肿瘤血管生成过程中，过度激活的 Wnt/β-catenin 信号持续诱导促血管生成因子的上调。此外，Wnt/β-catenin 信号的突变和过度激活与包括乳腺癌、宫颈癌和神经胶质瘤在内的几种人类癌症的不良预后相关。因此，Wnt/β-catenin 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检测和实验已经证明了化疗药物如阻断癌细胞周期、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的有前途的抗癌疗效。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。在此，我们综述了目前 Wnt/β-catenin 信号通路的小分子抑制剂，重点介绍了 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。我们描述了这些小分子在临床前和临床试验中治疗癌症时的结构、机制和功能。我们还综述了几种被报道具有抗血管生成作用的 Wnt/β-catenin 抑制剂。最后，我们解释了在人类癌症治疗中靶向 Wnt/β-catenin 信号通路的各种挑战，并提出了针对人类癌症的潜在治疗方法。
