2. Academic Validation
  3. Iron chelator deferasirox inhibits NF-κB activity in hepatoma cells and changes sorafenib-induced programmed cell deaths

Iron chelator deferasirox inhibits NF-κB activity in hepatoma cells and changes sorafenib-induced programmed cell deaths

  • Biomed Pharmacother. 2022 Sep;153:113363. doi: 10.1016/j.biopha.2022.113363.
Wataru Jomen 1,  Takaaki Ohtake 2,  Takayuki Akita 3,  Daisuke Suto 4,  Hideki Yagi 5,  Yosuke Osawa 6,  Yutaka Kohgo 6
Affiliations

Affiliations

  • 1 Department of Clinical Medical Sciences, International University of Health and Welfare Graduate School of Medicine, Tokyo, Japan.
  • 2 Department of Gastroenterology, International University of Health and Welfare School of Medicine, Narita, Japan; Department of Gastroenterology and Hepatology, International University of Health and Welfare Hospital, Nasushiobara, Japan. Electronic address: totake@iuhw.ac.jp.
  • 3 Department of Clinical Medical Sciences, International University of Health and Welfare Graduate School of Medicine, Tokyo, Japan; Department of Gastroenterology and Hepatology, International University of Health and Welfare Hospital, Nasushiobara, Japan.
  • 4 Department of Gastroenterology, International University of Health and Welfare School of Medicine, Narita, Japan; Department of Gastroenterology and Hepatology, International University of Health and Welfare Hospital, Nasushiobara, Japan.
  • 5 Department of Pharmaceutical, Faculty of Pharmacy, International University of Health and Welfare, Otawara, Japan.
  • 6 Department of Clinical Medical Sciences, International University of Health and Welfare Graduate School of Medicine, Tokyo, Japan; Department of Gastroenterology, International University of Health and Welfare School of Medicine, Narita, Japan; Department of Gastroenterology and Hepatology, International University of Health and Welfare Hospital, Nasushiobara, Japan.
PMID: 35834989 DOI: 10.1016/j.biopha.2022.113363
Abstract

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.

Keywords

Deferasirox; Ferroptosis; Hepatocellular carcinoma; NF-κB; Programmed cell death; Sorafenib.

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