Chen Han, Deng Jiao, Hou Tie-Wei, Shan Yong-Qi
Department of Pharmacy, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City, 110016, Liaoning Province, China.
Department of General Surgery, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang City, 110016, Liaoning Province, China.
J Ethnopharmacol. 2024 May 10;325:117907. doi: 10.1016/j.jep.2024.117907. Epub 2024 Feb 10.
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.
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.
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.
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.
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.
白花败酱（Patrinia villosa (Juss.)，PV）是中医治疗结直肠癌（CRC）的首选药物，且在临床上已取得可靠疗效。白花败酱醇是PV中的活性成分。然而，白花败酱醇逆转CRC化疗耐药性的分子机制尚不清楚。
通过网络药理学技术和实验验证白花败酱醇（PV的活性成分）通过调节CDKN2A基因逆转CRC/5-氟尿嘧啶（5-FU）耐药性的分子机制。
通过基因芯片分析，我们确定CDKN2A为与5-FU耐药相关的基因。接下来，我们在细胞系、动物样本和异种移植模型中进行了一系列功能分析，以研究CDKN2A在CRC的5-FU耐药中的作用、临床意义及异常调控机制。此外，我们筛选并获得了一种靶向CDKN2A的原料成分白花败酱醇，并研究了其药理作用。
对CRC细胞和动物样本的分析表明，CDKN2A表达上调与5-FU耐药密切相关。过表达CDKN2A的CRC细胞对5-FU的敏感性降低，且在体外具有更强的肿瘤生物学特性。抑制CDKN2A的异常激活可增强TP53的表达。机制上，CDKN2A的过表达激活PI3K/Akt通路并诱导对5-FU的耐药性。白花败酱醇抑制CDKN2A，使CRC/5-FU细胞恢复对5-FU的敏感性。白花败酱醇通过CDKN2A-TP53-PI3K/Akt轴有效逆转5-FU耐药。
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，用白花败酱醇抑制CDKN2A激活可能为临床克服5-FU耐药提供一种新方法。
