Journal Article

DKFZ-2025-00110

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Glucosylceramide Synthase Inhibition in Combination with Aripiprazole Sensitizes Hepatocellular Cancer Cells to Sorafenib and Doxorubicin.

Jennemann, R. (First author)DKFZ* ; Volz, M.DKFZ* ; Frias-Soler, R. C.DKFZ* ; Schulze, A.DKFZ* ; Richter, K.DKFZ* ; Kaden, S.DKFZ* ; Sandhoff, R. (Last author)DKFZ*

2025
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms26010304

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.

Keyword(s): Humans (MeSH) ; Carcinoma, Hepatocellular: drug therapy (MeSH) ; Carcinoma, Hepatocellular: pathology (MeSH) ; Carcinoma, Hepatocellular: metabolism (MeSH) ; Sorafenib: pharmacology (MeSH) ; Liver Neoplasms: drug therapy (MeSH) ; Liver Neoplasms: pathology (MeSH) ; Liver Neoplasms: metabolism (MeSH) ; Glucosyltransferases: antagonists & inhibitors (MeSH) ; Glucosyltransferases: metabolism (MeSH) ; Doxorubicin: pharmacology (MeSH) ; Aripiprazole: pharmacology (MeSH) ; Cell Line, Tumor (MeSH) ; Drug Synergism (MeSH) ; Cell Proliferation: drug effects (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: metabolism (MeSH) ; Antineoplastic Agents: pharmacology (MeSH) ; Genz ; anti-psychotic drugs ; aripiprazole ; cationic amphiphilic drugs (CAD) ; doxorubicin ; glucosylceramide synthase ; hepatocellular tumor spheroids ; lysosomal function ; mitochondrial function ; sorafenib ; Sorafenib ; Glucosyltransferases ; Doxorubicin ; Aripiprazole ; ceramide glucosyltransferase ; Antineoplastic Agents

Note: DKFZ-ZMBH Alliance / #EA:A411#LA:A411#

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Contributing Institute(s):

1. Lipid-Pathobiochemie (A411)
2. Metabolismus und Microenvironment (A410)
3. Elektronenmikroskopie (W230)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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