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@ARTICLE{Liese:163644,
      author       = {J. Liese$^*$ and T. M. Hinrichs and M. Lange and S.
                      Fulda$^*$},
      title        = {{C}otreatment with sorafenib and oleanolic acid induces
                      reactive oxygen species-dependent and mitochondrial-mediated
                      apoptotic cell death in hepatocellular carcinoma cells.},
      journal      = {Anti-cancer drugs},
      volume       = {30},
      number       = {3},
      issn         = {0959-4973},
      address      = {[S.l.]},
      publisher    = {Ovid},
      reportid     = {DKFZ-2020-01925},
      pages        = {209 - 217},
      year         = {2019},
      abstract     = {Hepatocellular carcinoma (HCC) is the most common liver
                      malignancy, and the lack of effective chemotherapies
                      underlines the need for novel therapeutic approaches for
                      this disease. Recently, we discovered a novel synergistic
                      induction of cell death by combining sorafenib, the only
                      routinely used palliative chemotherapeutic agent, and the
                      triterpenoid oleanolic acid (OA). However, the underlying
                      mechanisms of action have remained obscure. Here, we report
                      that sorafenib and OA acted in concert to trigger
                      mitochondria-mediated apoptotic cell death, which is
                      dependent on reactive oxygen species (ROS). Sorafenib/OA
                      cotreatment significantly increased ROS production, which
                      was prevented by the ROS scavengers α-tocopherol and
                      MnTBAP. Importantly, rescue experiments showed that ROS were
                      required for sorafenib/OA-induced apoptosis as ROS
                      scavengers protected HCC cells against cell death. In
                      addition, sorafenib and OA cotreatment cooperated to
                      decrease myeloid cell leukaemia-1 expression and to activate
                      Bak, two events that were prevented by ROS scavengers. Bak
                      activation was accompanied by the loss of mitochondrial
                      membrane potential, followed by PARP cleavage, DNA
                      fragmentation and, finally, apoptotic cell death in HCC
                      cells. By providing new insights into the molecular
                      regulation of sorafenib/OA-mediated and ROS-dependent cell
                      death, our study contributes toward the development of novel
                      treatment strategies to overcome sorafenib resistance in
                      HCC.},
      keywords     = {Antineoplastic Agents: pharmacology / Apoptosis /
                      Carcinoma, Hepatocellular: drug therapy / Carcinoma,
                      Hepatocellular: metabolism / Carcinoma, Hepatocellular:
                      pathology / Cell Proliferation / Drug Therapy, Combination /
                      Humans / Liver Neoplasms: drug therapy / Liver Neoplasms:
                      metabolism / Liver Neoplasms: pathology / Membrane
                      Potential, Mitochondrial: drug effects / Mitochondria: drug
                      effects / Mitochondria: metabolism / Mitochondria: pathology
                      / Oleanolic Acid: pharmacology / Reactive Oxygen Species:
                      metabolism / Sorafenib: pharmacology / Tumor Cells, Cultured
                      / Antineoplastic Agents (NLM Chemicals) / Reactive Oxygen
                      Species (NLM Chemicals) / Oleanolic Acid (NLM Chemicals) /
                      Sorafenib (NLM Chemicals)},
      cin          = {L501},
      ddc          = {610},
      cid          = {I:(DE-He78)L501-20160331},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30640794},
      doi          = {10.1097/CAD.0000000000000750},
      url          = {https://inrepo02.dkfz.de/record/163644},
}