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Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma.
Transl Oncol. 2020 Aug; 13(8):100785.TO

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.

Authors+Show Affiliations

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 60528, Frankfurt, Germany; Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.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.Institute 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.Institute 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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32416440

Citation

Lippmann, Jana, et al. "Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma." Translational Oncology, vol. 13, no. 8, 2020, p. 100785.
Lippmann J, Petri K, Fulda S, et al. Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma. Transl Oncol. 2020;13(8):100785.
Lippmann, J., Petri, K., Fulda, S., & Liese, J. (2020). Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma. Translational Oncology, 13(8), 100785. https://doi.org/10.1016/j.tranon.2020.100785
Lippmann J, et al. Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma. Transl Oncol. 2020;13(8):100785. PubMed PMID: 32416440.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma. AU - Lippmann,Jana, AU - Petri,Kathrin, AU - Fulda,Simone, AU - Liese,Juliane, Y1 - 2020/05/13/ PY - 2020/01/21/received PY - 2020/04/11/revised PY - 2020/04/13/accepted PY - 2020/5/18/pubmed PY - 2020/5/18/medline PY - 2020/5/17/entrez SP - 100785 EP - 100785 JF - Translational oncology JO - Transl Oncol VL - 13 IS - 8 N2 - 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. SN - 1936-5233 UR - https://www.unboundmedicine.com/medline/citation/32416440/Redox_Modulation_and_Induction_of_Ferroptosis_as_a_New_Therapeutic_Strategy_in_Hepatocellular_Carcinoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S1936-5233(20)30021-8 DB - PRIME DP - Unbound Medicine ER -
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