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@ARTICLE{Noack:119997,
      author       = {J. Noack$^*$ and J. Choi$^*$ and K. Richter$^*$ and A.
                      Kopp-Schneider$^*$ and A. Régnier-Vigouroux$^*$},
      title        = {{A} sphingosine kinase inhibitor combined with temozolomide
                      induces glioblastoma cell death through accumulation of
                      dihydrosphingosine and dihydroceramide, endoplasmic
                      reticulum stress and autophagy.},
      journal      = {Cell death $\&$ disease},
      volume       = {5},
      number       = {9},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2017-00585},
      pages        = {e1425 -},
      year         = {2014},
      abstract     = {Glioblastomas (GBMs) are very aggressive tumors with low
                      chemosensitivity. The DNA-alkylating agent temozolomide
                      (TMZ) is currently the most efficient chemotoxic drug for
                      GBM therapy; however, many patients develop resistance to
                      TMZ. Combining TMZ with another agent could present an
                      improved treatment option if it could overcome TMZ
                      resistance and avoid side effects. Sphingosine kinase
                      inhibitors (SKIs) have emerged as anticancer agents.
                      Sphingosine kinases are often overexpressed in tumors where
                      their activity of phosphorylating sphingosine (Sph)
                      contributes to tumor growth and migration. They control the
                      levels of the pro-apoptotic ceramide (Cer) and Sph and of
                      the pro-survival sphingosine-1 phosphate. In the present
                      work, TMZ was combined with a specific SKI, and the
                      cytotoxic effect of each drug alone or in combination was
                      tested on GBM cell lines. The combination of sublethal doses
                      of both agents resulted in the cell death potentiation of
                      GBM cell lines without affecting astrocyte viability. It
                      triggered a caspase-3-dependent cell death that was preceded
                      by accumulation of dihydrosphingosine (dhSph) and
                      dihydroceramide (dhCer), oxidative stress, endoplasmic
                      reticulum stress, and autophagy. Autophagy was identified as
                      the crucial switch that facilitated induction of this cell
                      death potentiation. The sublethal dose of the inhibitor
                      induced these stress events, whereas that of TMZ induced the
                      destructive autophagy switch. Remarkably, neither Cer nor
                      Sph, but rather the Cer intermediates, dhSph and dhCer, was
                      involved in the cytotoxicity from the combination. Cell
                      lines sensitive to the combination expressed low levels of
                      the antioxidant enzyme glutathione peroxidase-1, indicating
                      this enzyme as a potential marker of sensitivity to such
                      treatment. This work shows for the first time a strong
                      interaction between a SKI and TMZ, leading to a tumor
                      cell-specific death induction. It further demonstrates the
                      biological relevance of dihydrosphingolipids in cell death
                      mechanisms and emphasizes the potential of drugs that affect
                      sphingolipid metabolism for cancer therapy.},
      keywords     = {Antineoplastic Agents (NLM Chemicals) / Ceramides (NLM
                      Chemicals) / Enzyme Inhibitors (NLM Chemicals) /
                      dihydroceramide (NLM Chemicals) / Dacarbazine (NLM
                      Chemicals) / Phosphotransferases (Alcohol Group Acceptor)
                      (NLM Chemicals) / sphingosine kinase (NLM Chemicals) /
                      Sphingosine (NLM Chemicals) / safingol (NLM Chemicals) /
                      temozolomide (NLM Chemicals)},
      cin          = {C060},
      ddc          = {570},
      cid          = {I:(DE-He78)C060-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25255218},
      pmc          = {pmc:PMC4540206},
      doi          = {10.1038/cddis.2014.384},
      url          = {https://inrepo02.dkfz.de/record/119997},
}