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@ARTICLE{Wang:864928,
      author       = {Wang, Chenyin and Engelke, Laura and Bickel, David and
                      Hamacher, Alexandra and Frank, Marian and Proksch, Peter and
                      Gohlke, Holger and Kassack, Matthias U.},
      title        = {{T}he tetrahydroxanthone-dimer phomoxanthone {A} is a
                      strong inducer of apoptosis in cisplatin-resistant solid
                      cancer cells},
      journal      = {Bioorganic $\&$ medicinal chemistry},
      volume       = {27},
      number       = {19},
      issn         = {0968-0896},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2019-04531},
      pages        = {115044},
      year         = {2019},
      abstract     = {Platinum compounds are the first-line therapy for many
                      types of cancer. However, drug resistance has frequently
                      been reported for and is a major limitation of
                      platinum-based chemotherapy in the clinic. In the current
                      study, we examined the anti-tumor activity of phomoxanthone
                      A (PXA), a tetrahydroxanthone dimer isolated from the
                      endophytic fungus Phomopsis longicolla, in several solid
                      cancer cell lines and their cisplatin-resistant sub-cell
                      lines. PXA showed strong cytotoxic effects with IC50 values
                      in the high nanomolar or low micromolar range in MTT assays.
                      IC50 values of PXA were lower than those of cisplatin.
                      Remarkably, equipotent anti-cancer activity was found in
                      cisplatin-sensitive and respective cisplatin-resistant
                      cells. Anticancer effects of PXA were studied in further
                      detail in ovarian cancer (A2780) and bladder cancer (J82)
                      cell pairs. PXA led to rapid depolarization of the
                      mitochondrial membrane potential and strong activation of
                      caspase 3 and 7, eventually resulting in strong induction of
                      apoptosis. These effects occurred again both in sensitive
                      and resistant cell lines. IC50 values of PXA from MTT and
                      mitochondrial membrane depolarization assays were in good
                      agreement. Configurational free energy computations indicate
                      that both the neutral and singly negatively charged PXA show
                      membrane partitioning and can penetrate the inner
                      mitochondrial membrane. PXA treatment did not damage the
                      plasma membranes of cancer cells, thus excluding unspecific
                      membrane effects. Further, PXA had neither an effect on
                      intracellular ROS nor on reduction of ROS after hydrogen
                      peroxide treatment. In conclusion, our studies present PXA
                      as a natural compound with strong apoptotic anticancer
                      effects against platinum-resistant solid cancers. This may
                      open new treatment options in clinically resistant
                      malignancies.},
      cin          = {JSC / NIC / ICS-6},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31443950},
      UT           = {WOS:000484396400012},
      doi          = {10.1016/j.bmc.2019.115044},
      url          = {https://juser.fz-juelich.de/record/864928},
}