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

Jinrong Chang,Yamei Liu,Hui Li,Hoileong Wong Xavier,Zhaoxiang Bian,Dongfeng Chen

doi:10.3389/fphar.2021.690501

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.

Highlights

Colorectal cancer (CRC) is the third cause of cancer-related death worldwide according to the latest statistics of the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) (Authors Anonymous, 2021a)
We focused on ongoing strategies of Traditional Chinese medicines (TCMs) used to target aberrant Wnt/β-catenin pathway compared with targeted small molecules as a novel therapeutic intervention in different stages of CRC
Chemotherapy-induced side effects and drug resistance remain a major issue for clinical practice

Summary

INTRODUCTION

Colorectal cancer (CRC) is the third cause of cancer-related death worldwide according to the latest statistics of the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) (Authors Anonymous, 2021a). Several studies uncovered potential relations between Wnt pathway and non-coding microRNAs in CSCs. Scientists have discovered miR-142 can inhibit stem cell-like traits by targeting APC gene whose mutations are linked to colon cancer (Isobe et al, 2014). Scientists have discovered miR-142 can inhibit stem cell-like traits by targeting APC gene whose mutations are linked to colon cancer (Isobe et al, 2014) Taken together, these findings indicate that canonical WNT signaling plays a vital role in the maintenance and expansion of CSCs in CRC. These findings suggest that WD can selectively kill cancer cells with aberrant activation of Wnt signaling (Hao et al, 2013) Other small molecules, such as NSC668036 and Pen-N3, block the Wnt signaling pathway through binding to the Dishevelled (Dvl) PDZ domain and interrupting the receptor Frizzled (Fz)-Dvl interaction in colon cells (Shan et al, 2005; Zhang et al, 2009). Ewan K et al revealed that three small molecule inhibitors including CCT031374, CCT036477, and CCT070535 can block the Wnt/β-catenin signaling through reducing the level of ß-catenin without altering its stability, which

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CONCLUSIONS AND FUTURE PERPECTIVES