ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1586578
Synergistic effect of regorafenib with aminoglycosides ferroptosis mediated liver injury
Provisionally accepted
- 1Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, China
- 2National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China, Hangzhou 310058, China
- 3Jinhua Institute of Zhejiang University, Jinhua, 321036, China, Jinhua, 321036, China
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Background: Combination therapy of anticancer with antibacterial agents has numerous advantages, but these may develop adverse drug events that were rarely studied. Specifically, regorafenib mediates ferroptosis and causes liver injury when used with aminoglycosides; it was unexplored.The study was conducted on an in vivo and in vitro assay in which Sprague Dawley rats and HepG2/Huh7 were utilized to investigate ferroptosis-associated liver injury. The drugs regorafenib, amikacin, and gentamycin were administered individually as well as in combination with each other to evaluate noxious effects on the liver. Subsequently, biochemical, histological, transcriptomic analyses and protein expressions were investigated using immunoblotting assay to explore the mechanism underlying ferroptotic-mediated liver injury.The findings of the in-vivo assay revealed that combination therapy of regorafenib with aminoglycosides augments alanine transaminase (180% to 200%), aspartate aminotransferase (120% to 140%), malondialdehyde, and Fe 2+ level. It decreases the level of antioxidants and alters histomorphology in Sprague Dawley rats compared to individual therapy. The determinations of the in vitro assay validate enhanced levels of cellular iron, lipid peroxidation, reactive oxygen species, and lactate dehydrogenase release toxicity. In contrast, it decreased the cell viability ratio, glutathione level, and integrity of the mitochondrial membrane. The real-time quantitative poly chain reaction and immunoblotting assay results show down-regulation of GPX4, SLC7A11, and elevation of ALOX-15 (3 to 6-fold change).It has been concluded that 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.
Keywords: ferroptosis, Regorafenib, antibiotics, ALOX-15, Oxidative Stress, chemotherapy
Received: 03 Mar 2025; Accepted: 19 Jun 2025.
Copyright: © 2025 Raja, Zhou, HU, Lei, Zeng and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lushan Yu, Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 31005, Zhejiang Province, China
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