TY  - JOUR
AU  - Jennemann, Richard
AU  - Volz, Martina
AU  - Frias-Soler, Roberto Carlos
AU  - Schulze, Almut
AU  - Richter, Karsten
AU  - Kaden, Sylvia
AU  - Sandhoff, Roger
TI  - Glucosylceramide Synthase Inhibition in Combination with Aripiprazole Sensitizes Hepatocellular Cancer Cells to Sorafenib and Doxorubicin.
JO  - International journal of molecular sciences
VL  - 26
IS  - 1
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2025-00110
SP  - 304
PY  - 2025
N1  - DKFZ-ZMBH Alliance / #EA:A411#LA:A411#
AB  - 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.
KW  - Humans
KW  - Carcinoma, Hepatocellular: drug therapy
KW  - Carcinoma, Hepatocellular: pathology
KW  - Carcinoma, Hepatocellular: metabolism
KW  - Sorafenib: pharmacology
KW  - Liver Neoplasms: drug therapy
KW  - Liver Neoplasms: pathology
KW  - Liver Neoplasms: metabolism
KW  - Glucosyltransferases: antagonists & inhibitors
KW  - Glucosyltransferases: metabolism
KW  - Doxorubicin: pharmacology
KW  - Aripiprazole: pharmacology
KW  - Cell Line, Tumor
KW  - Drug Synergism
KW  - Cell Proliferation: drug effects
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Antineoplastic Agents: pharmacology
KW  - Genz (Other)
KW  - anti-psychotic drugs (Other)
KW  - aripiprazole (Other)
KW  - cationic amphiphilic drugs (CAD) (Other)
KW  - doxorubicin (Other)
KW  - glucosylceramide synthase (Other)
KW  - hepatocellular tumor spheroids (Other)
KW  - lysosomal function (Other)
KW  - mitochondrial function (Other)
KW  - sorafenib (Other)
KW  - Sorafenib (NLM Chemicals)
KW  - Glucosyltransferases (NLM Chemicals)
KW  - Doxorubicin (NLM Chemicals)
KW  - Aripiprazole (NLM Chemicals)
KW  - ceramide glucosyltransferase (NLM Chemicals)
KW  - Antineoplastic Agents (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39796160
C2  - pmc:PMC11720485
DO  - DOI:10.3390/ijms26010304
UR  - https://inrepo02.dkfz.de/record/296197
ER  -