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

Wnt/beta-catenin signalling is frequently activated in colorectal cancer, in which nuclear beta-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 beta-catenin without affecting its mRNA level, which suggests an alternative mechanism for beta-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 beta-catenin for the treatment of CRC patients.

Automated summary

This study synthesized novel stemona alkaloid analogues, among which compound 3 was found to efficiently inhibit various colorectal cancer cells, including drug-resistant cells, by reducing the protein level of beta-catenin without affecting its mRNA level. The downstream proteins expression was also significantly inhibited, suggesting potential for compound 3 as a destabilizer of beta-catenin for the treatment of colorectal cancer patients.