Andrographis overcomes 5-fluorouracil-associated chemoresistance through inhibition of DKK1 in colorectal cancer

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths in the USA. 5-Fluorouracil (5FU)-based chemotherapeutic drug remains a mainstay of CRC treatment. Unfortunately, similar to 50-60% of patients eventually develop resistance to 5FU, leading to poor survival outcomes. Our previous work revealed that andrographis enhanced 5FU-induced anti-cancer activity, but the underlying mechanistic understanding largely remains unclear. In this study, we first established 5FU-resistant (SFUR) CRC cells and observed that combined treatment with andrographis-SFU in SPUR cells exhibited superior effect on cell viability, proliferation, and colony formation capacity compared with individual treatments (P < 0.001). To identify key genes and pathways responsible for SFU resistance, we analyzed genome-wide transcriptomic profiling data from CRC patients who either responded or did not respond to 5FU. Among a panel of differentially expressed genes, Dickkopf-1 (DKK1) overexpression was a critical event for 5FU resistance. Moreover, andrographis significantly downregulated 5FU-induced DKK1 overexpression, accompanied with enhanced anti-tumor effects by abrogating downstream Akt-phosphorylation. In line with in vitro findings, andrographis enhanced 5FU-induced anti-cancer activity in mice xenografts and patient-derived tumoroids (P < 0.01). In conclusion, our data provide novel evidence for andrographis-mediated reversal of SFU resistance, highlighting its potential role as an adjunct to conventional chemotherapy in CRC.

Automated summary

The study indicates that andrographis can reverse resistance to 5FU, highlighting its potential role in the treatment of colorectal cancer.