瑞戈非尼与氨基糖苷类药物在铁死亡介导的肝损伤中的协同作用。

Synergistic effect of regorafenib with aminoglycosides in ferroptosis-mediated liver injury.

作者信息

Raja Dahar Maha, Zhou Shaojun, Hu Haihong, Lei Jinxiu, Zeng Kui, Yu Lushan

机构信息

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China.

出版信息

Front Pharmacol. 2025 Jul 15;16:1586578. doi: 10.3389/fphar.2025.1586578. eCollection 2025.

DOI:10.3389/fphar.2025.1586578

PMID:40735477

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12303813/

Abstract

BACKGROUND

Combination therapy of anticancer drugs with antibacterial agents has numerous advantages, but these may develop adverse drug events that were rarely studied. Specifically, regorafenib (REGO) mediates ferroptosis and causes liver injury when used in combination with aminoglycosides (AGs); however, this interaction remains unexplored.

METHODOLOGY

The study was conducted using both and assays involving Sprague-Dawley (SD) rats and HepG2/Huh7 to investigate ferroptosis-associated liver injury. The drugs REGO, amikacin (AMK), and gentamicin (GNT) were administered individually as well as in combination to evaluate their noxious effects on the liver. Subsequently, biochemical, histological, and transcriptomic analyses were carried out, and protein expressions were investigated using the immunoblotting assay to explore the mechanisms underlying ferroptotic-mediated liver injury.

RESULTS

The findings of the assay revealed that the combination therapy of regorafenib with aminoglycosides augments alanine transaminase (180%-200%), aspartate aminotransferase (120%-140%), malondialdehyde, and Fe levels. It decreases the level of antioxidants and alters histomorphology in SD rats compared to individual therapy. The assay results validate the enhanced levels of cellular iron, lipid peroxidation, reactive oxygen species, and lactate dehydrogenase release, indicating enhanced toxicity. In contrast, it decreased the cell viability ratio, glutathione level, and integrity of the mitochondrial membrane. The real-time quantitative polymerase chain reaction (RT-qPCR) and immunoblotting assay results show downregulation of GPX4 and SLC7A11 expressions, along with elevation of ALOX-15 (3- to 6-fold change).

CONCLUSION

Thus, combination therapy of regorafenib with amikacin and gentamycin causes significant elevation of iron and lipid peroxidation levels and alteration in protein expressions, which mediates ferroptotic cell death and leads to liver injury.

摘要

背景

抗癌药物与抗菌药物联合治疗有诸多优势，但可能会引发很少被研究的药物不良事件。具体而言，瑞戈非尼（REGO）与氨基糖苷类药物（AGs）联合使用时会介导铁死亡并导致肝损伤；然而，这种相互作用仍未得到探索。

方法

本研究使用涉及Sprague-Dawley（SD）大鼠和HepG2/Huh7细胞的实验和细胞实验来研究与铁死亡相关的肝损伤。分别单独及联合给予药物瑞戈非尼、阿米卡星（AMK）和庆大霉素（GNT），以评估它们对肝脏的有害影响。随后，进行生化、组织学和转录组分析，并使用免疫印迹法研究蛋白质表达，以探索铁死亡介导的肝损伤的潜在机制。

结果

实验结果显示，瑞戈非尼与氨基糖苷类药物联合治疗会使丙氨酸转氨酶（升高180%-200%）、天冬氨酸转氨酶（升高120%-140%）、丙二醛和铁水平升高。与单独治疗相比，这会降低SD大鼠体内抗氧化剂水平并改变组织形态。细胞实验结果证实了细胞内铁、脂质过氧化、活性氧水平升高以及乳酸脱氢酶释放增加，表明毒性增强。相反，它降低了细胞活力比率、谷胱甘肽水平和线粒体膜完整性。实时定量聚合酶链反应（RT-qPCR）和免疫印迹分析结果显示，谷胱甘肽过氧化物酶4（GPX4）和溶质载体家族7成员11（SLC7A11）表达下调，同时花生四烯酸脂氧合酶15（ALOX-15）表达升高（变化3至6倍）。