Evodiamine Enhances Chemosensitivity in Colorectal Cancer by Targeting Ribonucleotide Reductase M2

ABSTRACT Currently, chemotherapy in colorectal cancer (CRC) often leads to the development of drug resistance and poor prognosis. Prior research has shown that Evodiamine (Evo) exhibits antitumor properties; however, it has not been well studied in reversing tumor multidrug resistance (MDR). Therefore, this study's main objective is to explore Evo's capacity to overcome the resistance exhibited by colorectal cancer cells towards 5‐fluorouracil (5‐FU) and uncover the molecular mechanisms that underlie this phenomenon. The impact of Evo/5‐FU on cellular viability of colorectal cancer multidrug‐resistance (MDR) cell lines was detected by CCK8 assay, and Evo on the cell cycle as well as apoptosis of multidrug‐resistant (MDR) cells, both when Evo is administered alone and in combination with 5‐FU. Based on the RNA‐seq results, the possible targets of Evo were screened, the target genes were overexpressed and silenced, RT‐qPCR validated the mRNA expression, Western blot validated protein expression, and the associated phenotypic experiments were verified. The synergistic effect of Evo on 5‐FU was investigated using a colorectal cancer xenograft tumor model. The outcomes of in vivo and in vitro experiments demonstrated that low concentrations of Evo could markedly augment the growth inhibitory impact of 5‐FU on CRC cells compared to the group treated with 5‐FU alone. The mechanism potentially involves Evo targeting RRM2 to modulate the NF‐κB and JAK2/STAT3 pathways, thereby augmenting chemotherapeutic drug‐induced apoptosis. The findings suggest that Evo effectively reversed the multidrug resistance of HCT8/5‐FU cells in vitro and in vivo by targeting RRM2. The study also offers novel evidence to support further exploration of the potential anticancer properties of Evo.