Tectorigenin alleviates irinotecan-induced intestinal inflammation by activating the Nrf2/Keap1 pathway and synergistically enhances the anti-colon cancer efficacy of irinotecan

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-05-29 DOI:10.1016/j.taap.2025.117416

Rui Ma , Xiaoya Liu , Peng Zheng , Guijun Zou , Chaojun Zhang

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Abstract

Background

Gastrointestinal toxicity, primarily manifesting as colitis, is one of the most common adverse events during irinotecan (CPT-11) treatment for colon cancer, significantly impacting therapeutic efficacy and the general condition of patients. Tectorigenin (TEC) is a flavonoid compound extracted from Bupleurum and saponins, which are traditional Chinese medicines with anti-inflammatory properties. Previous experiments have found that it can alleviate CPT-11-induced diarrhoea and synergistically inhibit tumor growth with CPT-11, but the specific mechanisms remain unknown.

Methods

A CPT-11-induced diarrhoea mouse model was used to study the protective effect of TEC on CPT-11-induced diarrhoea in mouse by measuring levels of inflammatory cytokines and intestinal tight junction-related proteins in colon tissues. The chemopreventive effect of TEC was evaluated by measuring levels of inflammatory cytokines and intestinal tight junction-related proteins in Caco-2 cells exposed to CPT-11 and lipopolysaccharide (LPS). Finally, the synergistic effect of TEC combined with CPT-11 on tumor growth was investigated in a mouse model of colon tumors induced by subcutaneous implantation of CT26 colon cancer cells.

Results

TEC inhibited CPT-11-induced intestinal toxicity, as evidenced by reduced weight loss, decreased diarrhoea scores, and less intestinal shortening in mouse. Histological analysis demonstrated that TEC alleviated CPT-11-induced intestinal barrier damage. Additionally, TEC activated the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signalling pathway, reduced the expression of inflammatory cytokines both in vivo and in vitro, alleviated intestinal inflammation, and increased the expression of intestinal tight junction proteins, thereby enhancing intestinal barrier function. Furthermore, TEC exhibited a synergistic effect with CPT-11 in anti-tumor therapy.

Conclusions

This study confirmed that TEC alleviates CPT-11-induced intestinal inflammation by activating the Nrf2/Keap1 signalling pathway and enhances the anti-tumor effect of CPT-11 in colon cancer.

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鸢尾黄素通过激活Nrf2/Keap1通路减轻伊立替康诱导的肠道炎症，协同增强伊立替康的抗结肠癌疗效

胃肠道毒性是伊立替康（CPT-11）治疗结肠癌过程中最常见的不良事件之一，主要表现为结肠炎，严重影响治疗效果和患者的一般状况。Tectorigenin （TEC）是一种从柴胡和皂苷中提取的类黄酮化合物，是具有抗炎作用的中药。既往实验发现其可缓解CPT-11诱导的腹泻，并与CPT-11协同抑制肿瘤生长，但具体机制尚不清楚。方法采用cpt -11诱导腹泻小鼠模型，通过测定结肠组织炎症因子和肠紧密连接相关蛋白水平，研究TEC对cpt -11诱导腹泻小鼠的保护作用。通过测量暴露于CPT-11和脂多糖（LPS）的Caco-2细胞中炎症细胞因子和肠紧密连接相关蛋白的水平，评估TEC的化学预防作用。最后，在CT26结肠癌细胞皮下植入诱导的小鼠结肠肿瘤模型中，研究TEC联合CPT-11对肿瘤生长的协同作用。结果产志毒素大肠杆菌抑制cpt -11诱导的肠道毒性，小鼠体重减轻，腹泻评分降低，肠道缩短减少。组织学分析表明，TEC减轻了cpt -11诱导的肠屏障损伤。此外，TEC激活核因子红细胞2相关因子2/ kelch样ech相关蛋白1 （Nrf2/Keap1）信号通路，降低体内和体外炎症因子的表达，减轻肠道炎症，增加肠道紧密连接蛋白的表达，从而增强肠道屏障功能。此外，TEC在抗肿瘤治疗中表现出与CPT-11的协同作用。结论本研究证实，TEC通过激活Nrf2/Keap1信号通路减轻CPT-11诱导的肠道炎症，增强CPT-11在结肠癌中的抗肿瘤作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.