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@ARTICLE{Jennemann:296197,
      author       = {R. Jennemann$^*$ and M. Volz$^*$ and R. C. Frias-Soler$^*$
                      and A. Schulze$^*$ and K. Richter$^*$ and S. Kaden$^*$ and
                      R. Sandhoff$^*$},
      title        = {{G}lucosylceramide {S}ynthase {I}nhibition in {C}ombination
                      with {A}ripiprazole {S}ensitizes {H}epatocellular {C}ancer
                      {C}ells to {S}orafenib and {D}oxorubicin.},
      journal      = {International journal of molecular sciences},
      volume       = {26},
      number       = {1},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DKFZ-2025-00110},
      pages        = {304},
      year         = {2025},
      note         = {DKFZ-ZMBH Alliance / #EA:A411#LA:A411#},
      abstract     = {Hepatocellular carcinoma (HCC) is one of the leading causes
                      of cancer deaths due to its late diagnosis and restricted
                      therapeutic options. Therefore, the search for appropriate
                      alternatives to commonly applied therapies remains an area
                      of high clinical need. Here we investigated the therapeutic
                      potential of the glucosylceramide synthase (GCS) inhibitor
                      Genz-123346 and the cationic amphiphilic drug aripiprazole
                      on the inhibition of Huh7 and Hepa 1-6 hepatocellular cancer
                      cell and tumor microsphere growth. Single and combinatorial
                      treatments with both drugs at 5 µM concentration led to
                      efficient cell cycle arrest, reduced expression of cyclins A
                      and E, increased lipid storage in lysosomal compartments,
                      accompanied by increased uptake of lysotracker, and elevated
                      expression of the autophagy marker Lc3 II. Both drugs
                      affected mitochondrial function, indicated by altered
                      mitotracker uptake and impaired mitochondrial respiration.
                      Aripiprazole in monotherapy, or even more pronounced in
                      combination with Genz, also potentiated the effect of the
                      cytostatic drugs sorafenib and doxorubicin on tumor cell-
                      and tumor spheroid-growth inhibition. Targeting GCS with
                      Genz with the parallel application of cationic amphiphilic
                      drugs such as aripiprazole in combination with cytostatic
                      drugs may thus represent a potent therapeutic approach in
                      the treatment of HCC and potentially other cancer types.},
      keywords     = {Humans / Carcinoma, Hepatocellular: drug therapy /
                      Carcinoma, Hepatocellular: pathology / Carcinoma,
                      Hepatocellular: metabolism / Sorafenib: pharmacology / Liver
                      Neoplasms: drug therapy / Liver Neoplasms: pathology / Liver
                      Neoplasms: metabolism / Glucosyltransferases: antagonists
                      $\&$ inhibitors / Glucosyltransferases: metabolism /
                      Doxorubicin: pharmacology / Aripiprazole: pharmacology /
                      Cell Line, Tumor / Drug Synergism / Cell Proliferation: drug
                      effects / Mitochondria: drug effects / Mitochondria:
                      metabolism / Antineoplastic Agents: pharmacology / Genz
                      (Other) / anti-psychotic drugs (Other) / aripiprazole
                      (Other) / cationic amphiphilic drugs (CAD) (Other) /
                      doxorubicin (Other) / glucosylceramide synthase (Other) /
                      hepatocellular tumor spheroids (Other) / lysosomal function
                      (Other) / mitochondrial function (Other) / sorafenib (Other)
                      / Sorafenib (NLM Chemicals) / Glucosyltransferases (NLM
                      Chemicals) / Doxorubicin (NLM Chemicals) / Aripiprazole (NLM
                      Chemicals) / ceramide glucosyltransferase (NLM Chemicals) /
                      Antineoplastic Agents (NLM Chemicals)},
      cin          = {A411 / A410 / W230},
      ddc          = {540},
      cid          = {I:(DE-He78)A411-20160331 / I:(DE-He78)A410-20160331 /
                      I:(DE-He78)W230-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39796160},
      pmc          = {pmc:PMC11720485},
      doi          = {10.3390/ijms26010304},
      url          = {https://inrepo02.dkfz.de/record/296197},
}