Gegen Qinlian Decoction reverses oxaliplatin resistance in colorectal cancer by inhibiting YTHDF1-regulated m6A modification of GLS1.

BACKGROUND

Colorectal cancer (CRC) and its chemoresistance pose significant threats to human health. Gegen Qinlian Decoction (GQD) is frequently employed alongside chemotherapy drugs for the treatment of CRC and various intestinal disorders. Despite its widespread use, there is limited research investigating the mechanisms through which GQD reverses chemoresistance.

PURPOSE

This study investigated the mechanism by which GQD reverses oxaliplatin (OXA) resistance in CRC.

METHODS

A YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-knockdown OXA-resistant cell line was constructed by lentivirus to clarify YTHDF1-mediated chemoresistance through the regulation of glutaminase 1 (GLS1). The efficacy of GQD in reversing OXA resistance in CRC in vitro was evaluated by Cell Counting Kit-8, western blotting, quantitative real-time polymerase chain reaction, and glutaminase activity assays. In vivo validation was performed by constructing tumor xenografts in nude mice with OXA-resistant cells. In addition, mouse feces were collected and a 16S rDNA assay was performed to assess the regulation of intestinal flora by GQD.

RESULTS

Overexpression of YTHDF1 upregulated GLS1 expression and induced OXA-resistance in CRC. GQD induced apoptosis in LoVo/OXAR, increased OXA accumulation in LoVo/OXAR, inhibited expression of YTHDF1 and GLS1 when administered alone and in combination with OXA, and suppressed GLS1 activity to reverse drug resistance with good synergistic effects. GQD and OXA combination or GLS1 inhibitor alleviated OXA toxicity, reduced the volume of tumor xenografts in nude mice, inhibited YTHDF1 and GLS1 protein expression and GLS1 activity, adjusted the intestinal flora, and significantly reversed the increased Firmicutes/Bacteroidetes ratio.

CONCLUSION

GQD has shown superior efficacy in reversing OXA-resistance and increasing sensitivity. These findings indicate that the therapy combined with GQD has potential utility in the treatment of OXA-resistant CRC.