% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{OliverMetzig:129240,
      author       = {M. Oliver Metzig$^*$ and D. Fuchs$^*$ and K. Tagscherer$^*$
                      and H.-J. Gröne$^*$ and P. Schirmacher and W. Roth$^*$},
      title        = {{I}nhibition of caspases primes colon cancer cells for
                      5-fluorouracil-induced {TNF}-α-dependent necroptosis driven
                      by {RIP}1 kinase and {NF}-κ{B}.},
      journal      = {Oncogene},
      volume       = {35},
      number       = {26},
      issn         = {1476-5594},
      address      = {Basingstoke},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-05245},
      pages        = {3399 - 3409},
      year         = {2016},
      abstract     = {Resistance towards the drug 5-fluorouracil (5-FU) is a key
                      challenge in the adjuvant chemotherapy of colorectal cancer
                      (CRC), and novel targeted approaches are required to improve
                      the therapeutic outcome. Necroptosis is a recently
                      discovered form of programmed cell death, which depends on
                      receptor interacting protein 1 (RIP1) and particularly
                      occurs under caspase-deficient conditions. The targeted
                      induction of necroptosis represents a promising strategy to
                      overcome apoptosis resistance in cancer. The aim of this
                      study was to systematically explore the usage of pan-caspase
                      inhibitors to sensitize resistant CRC cells for 5-FU. We
                      found that pan-caspase inhibitors facilitated 5-FU-induced
                      necroptosis, which was mediated by autocrine secretion of
                      tumor necrosis factor α (TNF-α). TNF-α production was
                      driven by nuclear factor κB (NF-κB) and required RIP1
                      kinase. In vivo xenograft experiments showed that the novel
                      pan-caspase inhibitor IDN-7314 in combination with 5-FU
                      synergistically blocked tumor growth. Ex vivo experiments
                      with fresh human CRC tissue specimens further indicated that
                      a subgroup of patients could benefit from combinatory
                      treatment. Thereby, elevated levels of secreted TNF-α and
                      expression of components of the necroptotic pathway might
                      help to predict the sensitivity to pro-necroptotic
                      therapies. Together, our results shed new light on the
                      molecular regulation of necroptosis by NF-κB and RIP1.
                      Moreover, we identify necroptotic cell death as an important
                      effector mechanism of 5-FU-mediated anti-tumoral activity.
                      On the basis of this study, we propose pan-caspase
                      inhibitors as a novel approach in the adjuvant chemotherapy
                      of CRC.},
      keywords     = {Antimetabolites, Antineoplastic (NLM Chemicals) / NF-kappa
                      B (NLM Chemicals) / Oligopeptides (NLM Chemicals) /
                      Receptors, Tumor Necrosis Factor, Type I (NLM Chemicals) /
                      Tumor Necrosis Factor-alpha (NLM Chemicals) /
                      benzyloxycarbonyl-valyl-alanyl-aspartic acid (NLM Chemicals)
                      / RIPK1 protein, human (NLM Chemicals) /
                      Receptor-Interacting Protein Serine-Threonine Kinases (NLM
                      Chemicals) / Caspases (NLM Chemicals) / Fluorouracil (NLM
                      Chemicals)},
      cin          = {G150 / G130},
      ddc          = {610},
      cid          = {I:(DE-He78)G150-20160331 / I:(DE-He78)G130-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26522725},
      doi          = {10.1038/onc.2015.398},
      url          = {https://inrepo02.dkfz.de/record/129240},
}