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@ARTICLE{Kolbinger:136746,
      author       = {F. Kolbinger$^*$ and E. Koeneke$^*$ and J. Ridinger$^*$ and
                      T. Heimburg and M. Müller$^*$ and T. Bayer and W. Sippl and
                      M. Jung and N. Gunkel$^*$ and A. Miller$^*$ and F.
                      Westermann$^*$ and O. Witt$^*$ and I. Oehme$^*$},
      title        = {{T}he {HDAC}6/8/10 inhibitor {TH}34 induces {DNA}
                      damage-mediated cell death in human high-grade neuroblastoma
                      cell lines.},
      journal      = {Archives of toxicology},
      volume       = {92},
      number       = {8},
      issn         = {1432-0738},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2018-01184},
      pages        = {2649 - 2664},
      year         = {2018},
      abstract     = {High histone deacetylase (HDAC) 8 and HDAC10 expression
                      levels have been identified as predictors of exceptionally
                      poor outcomes in neuroblastoma, the most common extracranial
                      solid tumor in childhood. HDAC8 inhibition synergizes with
                      retinoic acid treatment to induce neuroblast maturation in
                      vitro and to inhibit neuroblastoma xenograft growth in vivo.
                      HDAC10 inhibition increases intracellular accumulation of
                      chemotherapeutics through interference with lysosomal
                      homeostasis, ultimately leading to cell death in cultured
                      neuroblastoma cells. So far, no HDAC inhibitor covering
                      HDAC8 and HDAC10 at micromolar concentrations without
                      inhibiting HDACs 1, 2 and 3 has been described. Here, we
                      introduce TH34 (3-(N-benzylamino)-4-methylbenzhydroxamic
                      acid), a novel HDAC6/8/10 inhibitor for neuroblastoma
                      therapy. TH34 is well-tolerated by non-transformed human
                      skin fibroblasts at concentrations up to 25 µM and
                      modestly impairs colony growth in medulloblastoma cell
                      lines, but specifically induces caspase-dependent programmed
                      cell death in a concentration-dependent manner in several
                      human neuroblastoma cell lines. In addition to the induction
                      of DNA double-strand breaks, HDAC6/8/10 inhibition also
                      leads to mitotic aberrations and cell-cycle arrest.
                      Neuroblastoma cells display elevated levels of neuronal
                      differentiation markers, mirrored by formation of
                      neurite-like outgrowths under maintained TH34 treatment.
                      Eventually, after long-term treatment, all neuroblastoma
                      cells undergo cell death. The combination of TH34 with
                      plasma-achievable concentrations of retinoic acid, a drug
                      applied in neuroblastoma therapy, synergistically inhibits
                      colony growth (combination index (CI) < 0.1 for 10 µM of
                      each). In summary, our study supports using selective HDAC
                      inhibitors as targeted antineoplastic agents and underlines
                      the therapeutic potential of selective HDAC6/8/10 inhibition
                      in high-grade neuroblastoma.},
      cin          = {G340 / L101 / G404 / B087},
      ddc          = {610},
      cid          = {I:(DE-He78)G340-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)G404-20160331 / I:(DE-He78)B087-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29947893},
      pmc          = {pmc:PMC6063332},
      doi          = {10.1007/s00204-018-2234-8},
      url          = {https://inrepo02.dkfz.de/record/136746},
}