title: Identification of a novel oxidative stress induced cell death by Sorafenib and oleanolic acid in human hepatocellular carcinoma cells.
abstract: The lack of effective chemotherapies in hepatocellular carcinoma (HCC) is still an unsolved problem and underlines the need for new strategies in liver cancer treatment. In this study, we present a novel approach to improve the efficacy of Sorafenib, today's only routinely used chemotherapeutic drug for HCC, in combination with triterpenoid oleanolic acid (OA). Our data show that cotreatment with subtoxic concentrations of Sorafenib and OA leads to highly synergistic induction of cell death. Importantly, Sorafenib/OA cotreatment triggers cell damage in a sustained manner and suppresses long-term clonogenic survival. Sorafenib/OA cotreatment induces DNA fragmentation and caspase-3/7 cleavage and the addition of the pan-caspase inhibitor zVAD.fmk shows the requirement of caspase activation for Sorafenib/OA-triggered cell death. Furthermore, Sorafenib/OA co-treatment stimulates a significant increase in reactive oxygen species (ROS) levels. Most importantly, the accumulation of intracellular ROS is required for cell death induction, since the addition of ROS scavengers (i.e. α-tocopherol, MnTBAP) that prevent the increase of intracellular ROS levels completely rescues cells from Sorafenib/OA-triggered cell death. In conclusion, OA represents a novel approach to increase the sensitivity of HCC cells to Sorafenib via oxidative stress.
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; General and Visceral Surgery, Goethe-University, Frankfurt, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
authors.forename: Behnaz Ahangarian
authors.initials: BA
authors.lastname: Abhari
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; General and Visceral Surgery, Goethe-University, Frankfurt, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hinrichs
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: simone.fulda@kgu.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; General and Visceral Surgery, Goethe-University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Liese
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D053179:Caspase 7 / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009828:Oleanolic Acid / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D061945:Caspase Inhibitors; D016166:Free Radical Scavengers; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; D009536:Niacinamide; D009828:Oleanolic Acid; D000077157:Sorafenib; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
keywords: Cell death; Hepatocellular carcinoma; Oleanolic acid; ROS; Redox; Sorafenib