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Iron chelator deferasirox inhibits NF-κB activity in hepatoma cells and changes sorafenib-induced programmed cell
Wataru Jomen1, Takaaki Ohtake2, Takayuki Akita3
1Department of Clinical Medical Sciences, International University of Health and Welfare Graduate School of Medicine, Tokyo, Japan.
Objective:
The improvements of antitumor effects and tolerability on chemotherapy for advanced hepatocellular carcinoma (HCC) are warranted. Here, we aimed to elucidate the mechanism of the combining effect of tyrosine kinase inhibitor sorafenib (SOR) and iron chelator deferasirox (DFX) in human hepatoma cell lines, HepG2 and Huh-7.
Methods:
The types of programmed cell deaths (PCDs); necrosis/necroptosis and apoptosis, were evaluated by flow cytometry and fluorescent microscopy. Human cleaved caspase-3 was analyzed by ELISA for apoptosis. GSH assay was used for ferroptosis. PCDs inhibition was analyzed by adding apoptosis inhibitor Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1, necroptosis inhibitor necrosulfonamide, respectively. The expression of NF-κB was quantified by Western blotting.
Results:
In SOR monotherapy, cleaved caspase-3 expression was increased in all concentrations, confirming the result that SOR induces apoptosis. In SOR monotherapy, GSH/GSSG ratio was decreased on concentration-dependent, showing that SOR also induced ferroptosis. Lipid Peroxidation caused by SOR, corresponding to ferroptosis, was suppressed by DFX. In fluorescence microscopy of SOR monotherapy, apoptosis was observed at a constant rate on all concentrations, while necroptosis and ferroptosis were increased on high concentration. In sorafenib and deferasirox combinations, sub G1 phase increased additively. In SOR and DFX combinations, the cytotoxic effects were not suppressed by ferrostatin-1, but suppressed by Z-VAD-FMK and necrosulfonamide. In each monotherapy, and SOR + DFX combinations, the expression of NF-κB in nucleus was suppressed. Regarding PCD by SOR and DFX combination, ferroptosis was suppressed and both apoptosis and necroptosis became dominant.
Conclusion:
Suppression of NF-κB is possibly involved in the effect of DFX. As a result, SOR and DFX combination showed additive antitumor effects for HCC through the mechanism of programed cell deaths and NF-kB signal modification.
Insights
Combining sorafenib (SOR) and deferasirox (DFX) enhances antitumor effects in advanced hepatocellular carcinoma (HCC). This combination therapy modifies programmed cell death pathways and NF-κB signaling for improved efficacy.
Area of Science:
- Hepatocellular Carcinoma Research
- Chemotherapy Mechanisms
- Molecular Targeted Therapy
Background:
- Advanced hepatocellular carcinoma (HCC) requires improved chemotherapy with better antitumor effects and tolerability.
- Tyrosine kinase inhibitors like sorafenib (SOR) and iron chelators like deferasirox (DFX) are potential therapeutic agents.
Purpose of the Study:
- To elucidate the combined mechanism of sorafenib (SOR) and deferasirox (DFX) in human hepatoma cell lines (HepG2 and Huh-7).
- To investigate the impact of this combination on programmed cell death (PCD) and NF-κB signaling.
Main Methods:
- Evaluation of programmed cell deaths (apoptosis, necroptosis, ferroptosis) using flow cytometry and fluorescent microscopy.
- Analysis of cleaved caspase-3 (apoptosis) by ELISA and GSH/GSSG ratio (ferroptosis) assays.
- Quantification of NF-κB expression via Western blotting and assessment of PCD inhibition using specific inhibitors.
Main Results:
- Sorafenib monotherapy induced apoptosis and ferroptosis, with increased necroptosis at higher concentrations.
- The combination of SOR and DFX demonstrated additive cytotoxic effects, with ferroptosis being suppressed.
- Apoptosis and necroptosis became dominant PCDs in the combination therapy, which also suppressed NF-κB nuclear expression.
Conclusions:
- The combination of sorafenib and deferasirox exhibits additive antitumor effects in HCC.
- This synergistic effect is mediated by modifications in programmed cell death pathways and NF-κB signaling.
- Deferasirox's role in suppressing NF-κB may contribute to the observed therapeutic benefits.
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