Potential Role of Traditional Chinese Medicines by Wnt/β-Catenin Pathway Compared With Targeted Small Molecules in Colorectal Cancer Therapy

Abstract

Colorectal cancer (CRC) has become a global public health problem because of its high incidence and mortality rate worldwide. The previous clinical treatment for CRC mainly involves conventional surgery, chemotherapy, and radiotherapy. With the development of tumor molecular targeted therapy, small molecule inhibitors present a great advantage in improving the survival of patients with advanced CRC. However, various side effects and drug resistance induced by chemotherapy are still the major obstacles to improve the clinical benefit. Thus, it is crucial to find new and alternative drugs for CRC treatment. Traditional Chinese medicines (TCMs) have been proved to have low toxicity and multi-target characteristics. In the last few decades, an increasing number of studies have demonstrated that TCMs exhibit strong anticancer effects in both experimental and clinical models and may serve as alternative chemotherapy agents for CRC treatment. Notably, Wnt/β-catenin signaling pathway plays a vital role in the initiation and progression of CRC by modulating the stability of β-catenin in the cytoplasm. Targeting Wnt/β-catenin pathway is a novel direction for developing therapies for CRC. In this review, we outlined the anti-tumor effects of small molecular inhibitors on CRC through Wnt/β-catenin pathway. More importantly, we focused on the potential role of TCMs against tumors by targeting Wnt/β-catenin signaling at different stages of CRC, including precancerous lesions, early stage of CRC and advanced CRC. Furthermore, we also discussed perspectives to develop potential new drugs from TCMs via Wnt/β-catenin pathway for the treatment of CRC.

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

“…46,47 Accordingly, Wnt/βcatenin signaling may serve as a therapeutic target for CRC, and some inhibitors of Wnt/β-catenin signaling show promising prospects for clinical application in CRC. 48 Here, we discovered that UA drastically lessened the expressions of Wnt4, β-catenin, TCF4, LEF1, and phosphorylated GSK-3β; promoted GSK-3β and phosphorylated β-catenin levels; and impeded nuclear translocation of β-catenin of CRC. Similarly, UA is reported to trigger apoptosis and repress the proliferation of lung carcinoma H1975 cells by negative modulation of the β-catenin/TCF4 signaling pathway.…”

“…The Wnt signaling pathway begins with the binding of the Wnt protein ligand to the cell membrane Frizzled family receptor, transducing the signal to Dvl (disheveled) protein within the cell. This route is largely conserved across species, from fruit flies to humans. − Deregulated Wnt/β-catenin signaling drives CRC pathogenesis. , Accordingly, Wnt/β-catenin signaling may serve as a therapeutic target for CRC, and some inhibitors of Wnt/β-catenin signaling show promising prospects for clinical application in CRC …”

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

“…The compound has been used as a pharmacological tool to block the Wnt/βcatenin pathway in different studies [46][47][48][49]. KYA1797K represents a prototypic inhibitor used to modulate the Wnt/β-catenin signaling pathway in various cancer models [50,51].…”

Delivery of Engineered Primary Tumor-Derived Exosomes Effectively Suppressed the Colorectal Cancer Chemoresistance and Liver Metastasis

“…The biological mechanism of CRCLM and chemotherapy resistance is highly complex, involving tumor heterogeneity and dysregulated gene expression. ,, Abnormal activation of Wnt/β-catenin and epithelial-mesenchymal transition pathways are involved in distant metastasis or chemoresistance of CRC, − and the use of Wnt signaling pathway inhibitors has demonstrated antitumor efficacy in preclinical studies. − However, the development of therapeutic resistance may be the ultimate cause of the poor prognosis associated with CRCLM. Due to tumor heterogeneity, the mechanisms of chemotherapy resistance in CRC are complex and not yet fully understood. − Therefore, it is critical to understand the underlying mechanisms and identify therapeutic targets for CRCLM and chemotherapy resistance in clinical specimens.…”