title: Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib.
abstract: The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC). In our report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors.
authors.affiliation: INSERM U1088, Faculté de Médecine, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Ezzoukhry
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barbare
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Mazière
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D003514:Cyclohexylamines / Q000494:pharmacology; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress; D010655:Phenylenediamines / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D017262:Siderophores / Q000737:chemistry; D000077157:Sorafenib; D048490:raf Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D010655:Phenylenediamines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D017262:Siderophores; C573944:ferrostatin-1; D009536:Niacinamide; D000077157:Sorafenib; D007501:Iron; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D035942:Iron Regulatory Protein 2; D003676:Deferoxamine
keywords: deferoxamine; ferroptosis; hepatocellular carcinoma; iron; sorafenib