A novel β-carboline alkaloid derivative targeting MDM2-p53 pathway suppresses colorectal cancer progression.

PURPOSE: Colorectal cancer (CRC) remains a major global health challenge, necessitating novel therapeutic approaches. β-carboline alkaloids, natural compounds with anticancer properties, have shown potential to inhibit cancer cell viability. Here, we synthesized β-carboline derivatives and explored their potential as CRC inhibitors. METHODS: The IC(50) values of β-carboline derivatives were determined by cell viability assay. The biological effects of the leading candidate were evaluated via cell cycle analysis, proliferation assay, colony formation, apoptosis assay, and reactive oxygen species detection. Mechanistic studies were performed using transcriptomic and proteomic analysis, validated by immunoblotting, pulldown assay, cycloheximide-chasing assay, and co-immunoprecipitation. An in vivo CRC xenograft model was used to assess the efficacy of the leading candidate. RESULTS: Z-7 was identified as the leading candidate due to its ability to induce apoptosis and cell cycle arrest in CRC cells. Transcriptomic and proteomic data revealed that Z-7 activated the p53 signaling pathway in p53 wild-type CRC by binding to MDM2 at the RING domain, and inhibiting the E3 ligase activity of MDM2, leading to the reduction of p53 ubiquitination. In vivo study showed Z-7 treatment elevated p53 expression and significantly suppressed tumor growth in xenograft models. CONCLUSION: Z-7 is a promising candidate for CRC therapy, particularly in patients with functional p53 and elevated MDM2, warranting further clinical evaluation.