背景:Patriniavillosa(Juss。)(PV)是中药治疗结直肠癌(CRC)的首选药物,在临床上取得了可靠疗效。Villosol是PV中的活性成分。然而,Villosol逆转CRC化学耐药的分子机制尚不清楚.
目的:分析Villosol,PV的活性成分,通过网络药理学技术和实验验证了通过调节CDKN2A基因逆转CRC/5-FU抗性。
方法:我们通过基因芯片分析将CDKN2A鉴定为与5-FU抗性相关的基因。接下来,我们在细胞系中进行了一系列功能分析,动物样本,和异种移植模型来研究其作用,临床意义,CDKN2A在CRC5-FU耐药中的异常调控机制。此外,我们筛选并获得了一种叫做Villosol的原料,以CDKN2A为目标,并研究了其药理作用。
结果:对CRC细胞和动物样本的分析表明,CDKN2A表达上调与5-FU抗性密切相关。过表达CDKN2A的CRC细胞在体外显示出对5-FU的敏感性降低和肿瘤生物学增强。抑制CDKN2A的异常活化增强TP53的表达。机械上,CDKN2A的过表达激活PI3K/Akt途径并诱导对5-FU的抗性。Villosol抑制CDKN2A,CRC/5-FU细胞恢复对5-FU的敏感性。Villosol通过CDKN2A-TP53-PI3K/Akt轴有效反转5-FU电阻。
结论:CDKN2A基因表达的变化可用于预测CRC患者对5-FU治疗的反应。此外,用Villosol抑制CDKN2A激活可能是在临床环境中克服5-FU抵抗的新方法。
BACKGROUND: Patrinia villosa (Juss.) (PV) is the drug of choice in traditional Chinese medicine for the treatment of colorectal cancer (CRC) and has achieved reliable efficacy in clinic. Villosol is the active ingredient in PV. However, the molecular mechanism by which Villosol reverses chemoresistance in CRC remains unclear.
OBJECTIVE: Analysis of the molecular mechanism by which Villosol, the active ingredient of PV, reverses CRC/5-FU resistance through modulation of the CDKN2A gene was validated by network pharmacology techniques and experiments.
METHODS: We identified CDKN2A as a gene associated with 5-FU resistance through gene chip analysis. Next, we conducted a series of functional analyses in cell lines, animal samples, and xenograft models to investigate the role, clinical significance, and abnormal regulatory mechanisms of CDKN2A in 5-FU resistance in CRC. In addition, we screened and obtained a raw ingredient called Villosol, which targets CDKN2A, and investigated its pharmacological effects.
RESULTS: Analysis of CRC cells and animal samples showed that the upregulation of CDKN2A expression was strongly associated with 5-FU resistance. CRC cells overexpressing CDKN2A showed reduced sensitivity to 5-FU and enhanced tumor biology in vitro. Inhibition of aberrant activation of CDKN2A enhances the expression of TP53. Mechanistically, overexpression of CDKN2A activates the PI3K/Akt pathway and induces resistance to 5-FU. Villosol inhibited CDKN2A, and CRC/5-FU cells regained sensitivity to 5-FU. Villosol effectively reverses 5-FU resistance through the CDKN2A-TP53-PI3K/Akt axis.
CONCLUSIONS: Changes in CDKN2A gene expression can be used to predict the response of CRC patients to 5-FU therapy. Additionally, inhibiting CDKN2A activation with Villosol may present a new approach to overcoming 5-FU resistance in clinical settings.