Ge Yuchen, Zhao Bingxiang, Li Man, Li Zhenglin, Bai Shirui, Zhang Qishan, Wang Xue, Wang Guangming, Cheng Jianjie, Wang Xiaobo
School of Basic Medicine, Dali University, Dali, Yunnan 671000, China; Department of Neurosurgery, the First Affiliated Hospital of Dali University, Dali, Yunnan 671000, China.
School of Basic Medicine, Dali University, Dali, Yunnan 671000, China.
Toxicol Appl Pharmacol. 2025 Sep;502:117404. doi: 10.1016/j.taap.2025.117404. Epub 2025 May 29.
Fluorouracil (Fu) is one of the first-line drugs for colorectal cancer, but severe intestinal damage limits its clinical application. The intestinal damage caused by Fu is closely related to cellular senescence. Itraconazole (Itr) is primarily used to treat fungal infections. At present, the effects of Itr on intestinal senescence and damage have not been the subject of extensive study. In this study, NCM460 cells were utilized to establish a model of Fu-induced senescence and inflammation. Treatment of NCM460 cells with Fu resulted in increased senescence-associated beta-galactosidase (SA-β-Gal) activity, elevated p21 expression, and the upregulation of p16 and p53. Additionally, there was enhanced Senescence-Associated Secretory Phenotype (SASP) and an increase in inflammatory factors IL-1β and IL-6. The present study demonstrated that the treatment of Itr effectively alleviated the changes caused by Fu in NCM460 cells. Moreover, it was observed that Itr was efficacious in mitigating intestinal damage induced by Fu in Balb/c mice. Network pharmacology analysis and experimental validation identified the mTOR signaling pathway as a key target of Itr in treating Fu-induced intestinal aging and inflammation. Our findings demonstrate that Itr significantly inhibited the mTOR pathway, while the mTOR activator MHY1485 restored mTOR activity and promoted senescence. Moreover, it was observed that Itr could effectively enhance the tumor-killing effect of Fu in HCT116 and SW480 cells, as well as in Balb/c nude mice. In conclusion, Itr is a promising candidate for reducing intestinal side effects and enhancing Fu's efficacy in the treatment of colorectal cancer.
氟尿嘧啶（Fu）是结直肠癌的一线用药之一，但严重的肠道损伤限制了其临床应用。Fu引起的肠道损伤与细胞衰老密切相关。伊曲康唑（Itr）主要用于治疗真菌感染。目前，Itr对肠道衰老和损伤的影响尚未得到广泛研究。在本研究中，利用NCM460细胞建立了Fu诱导的衰老和炎症模型。用Fu处理NCM460细胞导致衰老相关β-半乳糖苷酶（SA-β-Gal）活性增加、p21表达升高以及p16和p53上调。此外，衰老相关分泌表型（SASP）增强，炎症因子IL-1β和IL-6增加。本研究表明，Itr处理可有效减轻Fu在NCM460细胞中引起的变化。此外，观察到Itr在减轻Balb/c小鼠中Fu诱导的肠道损伤方面有效。网络药理学分析和实验验证确定mTOR信号通路是Itr治疗Fu诱导的肠道衰老和炎症的关键靶点。我们的研究结果表明，Itr显著抑制mTOR通路，而mTOR激活剂MHY1485恢复mTOR活性并促进衰老。此外，观察到Itr可有效增强Fu对HCT116和SW480细胞以及Balb/c裸鼠的肿瘤杀伤作用。总之，Itr是减少肠道副作用并增强Fu在结直肠癌治疗中疗效的有前景的候选药物。
