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@ARTICLE{Gambichler:276860,
      author       = {T. Gambichler and B. Majchrzak-Stiller and I. Peters and J.
                      Becker$^*$ and J. Strotmann and N. Abu Rached and T. Müller
                      and W. Uhl and M. Buchholz and C. Braumann},
      title        = {{T}he effect of {GP}-2250 on cultured virus-negative
                      {M}erkel cell carcinoma cells: preliminary results.},
      journal      = {Journal of cancer research and clinical oncology},
      volume       = {149},
      number       = {12},
      issn         = {0301-1585},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2023-01172},
      pages        = {10831-10840},
      year         = {2023},
      note         = {2023 Sep;149(12):10831-10840},
      abstract     = {Even in the novel immunotherapy era, Merkel cell carcinoma
                      (MCC) remains challenging in its treatment. Apart from
                      Merkel cell polyomavirus (MCPyV) associated MCC, this cancer
                      is linked in about $20\%$ of cases to ultraviolet-induced
                      mutational burden frequently causing aberrations in Notch
                      and PI3K/AKT/mTOR signalling pathways. The recently
                      developed agent GP-2250 is capable to inhibit growth of
                      cells of different cancers, including pancreatic
                      neuroendocrine tumors. The objective of the present study
                      was to investigate the effects of GP-2250 on MCPyV-negative
                      MCC cells.Methods We employed three cell lines (MCC13,
                      MCC14.2, MCC26) which were exposed to different
                      GP-2250doses. GP-2250's effects on cell viability,
                      proliferation, and migration were evaluated by means of MTT,
                      BrdU, and scratch assays, respectively. Flow cytometry was
                      performed for the evaluation of apoptosis and necrosis.
                      Western blotting was implemented for the determination of
                      AKT, mTOR, STAT3, and Notch1 protein expression.Cell
                      viability, proliferation, and migration decreased with
                      increasing GP-2250 doses. Flow cytometry revealed a dose
                      response to GP-2250 in all three MCC cell lines. While the
                      viable fraction decreased, the share of necrotic and in a
                      smaller amount the apoptotic cells increased. Regarding
                      Notch1, AKT, mTOR, and STAT3 expression a comparatively
                      time- and dose-dependent decrease of protein expression in
                      the MCC13 and MCC26 cell lines was observed. By contrast,
                      Notch1, AKT, mTOR, and STAT3 expression in MCC14.2 was
                      scarcely altered or even increased by the three dosages of
                      GP-2250 applied.The present study indicates GP-2250 having
                      anti-neoplastic effects in MCPyV-negative tumor cells in
                      regard to viability, proliferation, and migration. Moreover,
                      the substance is capable of downregulating protein
                      expression of aberrant tumorigenic pathways in
                      MCPyV-negative MCC cells.},
      keywords     = {Merkel cell carcinoma (Other) / Merkel cell polyomavirus
                      (Other) / Neuroendocrine tumor (Other) / Skin cancer
                      (Other)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37311987},
      doi          = {10.1007/s00432-023-04960-3},
      url          = {https://inrepo02.dkfz.de/record/276860},
}