2. Academic Validation
  3. Discovery of a potent β-catenin destabilizer for overcoming the resistance of 5-fluorouracil in colorectal cancer

Discovery of a potent β-catenin destabilizer for overcoming the resistance of 5-fluorouracil in colorectal cancer

  • Bioorg Med Chem. 2021 Jan 15:30:115929. doi: 10.1016/j.bmc.2020.115929.
Kaiqing Ma 1,  Mengchen Zhang 2,  Xingkang Wu 2,  Peng Yang 3,  Caixia Yin 4
Affiliations

Affiliations

  • 1 Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, China. Electronic address: makaiqing@sxu.edu.cn.
  • 2 Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, Shanxi 030006, China.
  • 3 Institute of Biotechnology, Shanxi University, Taiyuan, Shanxi 030006, China.
  • 4 Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, China.
PMID: 33321421 DOI: 10.1016/j.bmc.2020.115929
Abstract

Wnt/β-catenin signalling is frequently activated in colorectal Cancer, in which nuclear β-catenin accumulation contributes to tumour initiation and progression. However, therapeutic agents in clinical use targeting this pathway are lacking. In this report, we describe the synthesis of novel stemona alkaloid analogues and their biological evaluation, among which compound 3 was identified to efficiently inhibit various CRC cells, including 5-fluorouracil-resistant CRC cells. Mechanistically, this study revealed that compound 3 reduced the protein level of β-catenin without affecting its mRNA level, which suggests an alternative mechanism for β-catenin degradation. The expression of downstream proteins, including c-Myc, Survivin, and cyclin D1, was also significantly inhibited, even in Wnt-activated CRC cells. Briefly, our data highlight the potential of compound 3 as a destabilizer of β-catenin for the treatment of CRC patients.

Keywords

5-fluorouracil; Colorectal cancer; Destabilizer; Stemona alkaloid; Wnt; β-catenin.

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