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@ARTICLE{Isayev:125993,
      author       = {O. Isayev$^*$ and V. Rausch$^*$ and N. Bauer$^*$ and L.
                      Liu$^*$ and P. Fan$^*$ and Y. Zhang$^*$ and J. Gladkich$^*$
                      and C. Nwaeburu$^*$ and J. Mattern$^*$ and M. Mollenhauer
                      and F. Rückert and S. Zach and U. Haberkorn$^*$ and W.
                      Gross$^*$ and F. Schönsiegel$^*$ and A. V. Bazhin and I.
                      Herr$^*$},
      title        = {{I}nhibition of glucose turnover by 3-bromopyruvate
                      counteracts pancreatic cancer stem cell features and
                      sensitizes cells to gemcitabine.},
      journal      = {OncoTarget},
      volume       = {5},
      number       = {13},
      issn         = {1949-2553},
      address      = {[S.l.]},
      publisher    = {Impact Journals LLC},
      reportid     = {DKFZ-2017-02108},
      pages        = {5177 - 5189},
      year         = {2014},
      abstract     = {According to the cancer stem cell (CSC) hypothesis, the
                      aggressive growth and early metastasis of pancreatic ductal
                      adenocarcinoma (PDA) is due to the activity of CSCs, which
                      are not targeted by current therapies. Otto Warburg
                      suggested that the growth of cancer cells is driven by a
                      high glucose metabolism. Here, we investigated whether
                      glycolysis inhibition targets CSCs and thus may enhance
                      therapeutic efficacy. Four established and 3 primary PDA
                      cell lines, non-malignant cells, and 3 patient-tumor-derived
                      CSC-enriched spheroidal cultures were analyzed by glucose
                      turnover measurements, MTT and ATP assays, flow cytometry of
                      ALDH1 activity and annexin positivity, colony and spheroid
                      formation, western blotting, electrophoretic mobility shift
                      assay, xenotransplantation, and immunohistochemistry. The
                      effect of siRNA-mediated inhibition of LDH-A and LDH-B was
                      also investigated. The PDA cells exhibited a high glucose
                      metabolism, and glucose withdrawal or LDH inhibition by
                      siRNA prevented growth and colony formation. Treatment with
                      the anti-glycolytic agent 3-bromopyruvate almost completely
                      blocked cell viability, self-renewal potential, NF-κB
                      binding activity, and stem cell-related signaling and
                      reverted gemcitabine resistance. 3-bromopyruvate was less
                      effective in weakly malignant PDA cells and did not affect
                      non-malignant cells, predicting minimal side effects.
                      3-bromopyruvate inhibited in vivo tumor engraftment and
                      growth on chicken eggs and mice and enhanced the efficacy of
                      gemcitabine by influencing the expression of markers of
                      proliferation, apoptosis, self-renewal, and metastasis. Most
                      importantly, primary CSC-enriched spheroidal cultures were
                      eliminated by 3-bromopyruvate. These findings propose that
                      CSCs may be specifically dependent on a high glucose
                      turnover and suggest 3-bromopyruvate for therapeutic
                      intervention.},
      keywords     = {Antimetabolites, Antineoplastic (NLM Chemicals) /
                      Biomarkers, Tumor (NLM Chemicals) / Isoenzymes (NLM
                      Chemicals) / Pyruvates (NLM Chemicals) / Deoxycytidine (NLM
                      Chemicals) / bromopyruvate (NLM Chemicals) / gemcitabine
                      (NLM Chemicals) / L-Lactate Dehydrogenase (NLM Chemicals) /
                      Glucose (NLM Chemicals)},
      cin          = {G403 / E060},
      ddc          = {610},
      cid          = {I:(DE-He78)G403-20160331 / I:(DE-He78)E060-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25015789},
      pmc          = {pmc:PMC4148131},
      doi          = {10.18632/oncotarget.2120},
      url          = {https://inrepo02.dkfz.de/record/125993},
}