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  • Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro.

Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro.

International journal of molecular sciences (2020-04-05)
Katja Jakobi, Sandra Beyer, Alexander Koch, Dominique Thomas, Stephanie Schwalm, Stefan Zeuzem, Josef Pfeilschifter, Georgios Grammatikos
ABSTRACT

Hepatocellular carcinoma (HCC) shows a remarkable heterogeneity and is recognized as a chemoresistant tumor with dismal prognosis. In previous studies, we observed significant alterations in the serum sphingolipids of patients with HCC. This study aimed to investigate the in vitro effects of sorafenib, which is the most widely used systemic HCC medication, on the sphingolipid pathway as well as the effects of inhibiting the sphingolipid pathway in HCC. Huh7.5 and HepG2 cells were stimulated with sorafenib, and inhibitors of the sphingolipid pathway and cell proliferation, viability, and concentrations of bioactive metabolites were assessed. We observed a significant downregulation of cell proliferation and viability and a simultaneous upregulation of dihydroceramides upon sorafenib stimulation. Interestingly, fumonisin B1 (FB1) and the general sphingosine kinase inhibitor SKI II were able to inhibit cell proliferation more prominently in HepG2 and Huh7.5 cells, whereas there were no consistent effects on the formation of dihydroceramides, thus implying an involvement of distinct metabolic pathways. In conclusion, our study demonstrates a significant downregulation of HCC proliferation upon sorafenib, FB1, and SKI II treatment, whereas it seems they exert antiproliferative effects independently from sphingolipids. Certainly, further data would be required to elucidate the potential of FB1 and SKI II as putative novel therapeutic targets in HCC.

MATERIALS
Product Number
Brand
Product Description

Avanti
Sphinganine (d18:0), Avanti Research - A Croda Brand
Avanti
Sphingosine-1-Phosphate (d18:1), Avanti Research - A Croda Brand
Avanti
Sphinganine (d20:0), Avanti Research - A Croda Brand 860674P, powder
Avanti
Sphingosine (d20:1), Avanti Research - A Croda Brand 860660P, powder
Sigma-Aldrich
SKI II, ≥98% (HPLC), solid
Avanti
Sphingosine (d18:1), Avanti Research - A Croda Brand
Avanti
Sphinganine-1-Phosphate (d18:0), Avanti Research - A Croda Brand 860536P, powder
Sigma-Aldrich
SLM6031434 hydrochloride, ≥98% (HPLC)