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Abstract Details
Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma
Transl Oncol. 2020 Aug;13(8):100785. doi: 10.1016/j.tranon.2020.100785. Epub 2020 May 13.
Jana Lippmann1, Kathrin Petri2, Simone Fulda3, Juliane Liese4
Author information
1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 60528, Frankfurt, Germany; Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
2Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen Germany; Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen University, Giessen, Germany.
3Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 60528, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany; German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
4Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 60528, Frankfurt, Germany; Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen Germany; Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen University, Giessen, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany; German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Electronic address: Juliane.liese@chiru.med.uni-giessen.de.
Free PMC article
Abstract
Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC. In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC.