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Synergistic effect of regorafenib with aminoglycosides in ferroptosis-mediated liver injury
Maha Raja Dahar1,2, Shaojun Zhou1,2, Haihong Hu1,3
1Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
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 in vivo and in vitro 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 in vivo assay revealed that the combination therapy of regorafenib with aminoglycosides augments alanine transaminase (180%-200%), aspartate aminotransferase (120%-140%), malondialdehyde, and Fe2+ levels. It decreases the level of antioxidants and alters histomorphology in SD rats compared to individual therapy. The in vitro 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.
Insights
Regorafenib combined with aminoglycosides causes severe liver injury by inducing ferroptosis. This combination therapy significantly increases iron and lipid peroxidation, leading to cell death and organ damage.
Area of Science:
- Pharmacology
- Hepatology
- Toxicology
Background:
- Combination therapy of anticancer drugs with antibacterials offers benefits but may cause adverse drug events.
- Regorafenib (REGO) and aminoglycosides (AGs) interaction leading to ferroptosis-induced liver injury is unexplored.
Purpose of the Study:
- To investigate the ferroptosis-associated liver injury caused by the combination of regorafenib with aminoglycosides.
- To elucidate the underlying mechanisms of this drug interaction.
Main Methods:
- In vivo (Sprague-Dawley rats) and in vitro (HepG2/Huh7 cells) assays were employed.
- Biochemical, histological, and transcriptomic analyses, including RT-qPCR and immunoblotting, were performed.
Main Results:
- Combination therapy significantly elevated liver enzymes (ALT, AST), malondialdehyde, and Fe2+ levels, while decreasing antioxidants.
- In vitro studies showed increased cellular iron, lipid peroxidation, ROS, and LDH release, with decreased cell viability and glutathione.
- Downregulation of GPX4 and SLC7A11, and upregulation of ALOX-15 were observed.
Conclusions:
- Regorafenib and aminoglycoside combination therapy induces significant liver injury.
- This injury is mediated by ferroptosis, characterized by increased iron, lipid peroxidation, and altered protein expression.
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