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Sphingosine kinase inhibition sensitizes hepatocellular carcinoma cells to chemotherapy

Hepatocellular carcinoma (HCC) is a major challenge for medical oncologists because of its inherent chemoresistance. Common chemotherapy drugs used for the treatment of advanced HCC such as doxorubicin, cisplatin and 5-fluorouracil (5-FU) show low response rates. Novel targeted agent recently introduced into the HCC treatment, namely multikinase inhibitor sorafenib, also exhibited moderate efficacy in clinical studies. Therefore, there is an urgent need for innovative strategies that would provide significant clinical benefit to the HCC patients. Sphingosine kinase (SphK) is a key regulator of sphingolipid rheostat which balances between the two major bioactive interconvertible sphingolipids with opposing functions, namely pro-apoptotic ceramide and pro-proliferative sphingosine-1-phosphate. Importantly, SphK is found to be overexpressed in a variety of solid human tumours, which makes it a suitable target for pharmacological intervention. In the present work, we investigated the effect of dual sphingosine kinase isoenzyme inhibitor SK1-II (4-[[4-(4- chlorophenyl)-1, 3-thiazol-2-yl]amino]phenol on the ability of doxorubicin, cisplatin, 5-FU and sorafenib to inhibit proliferation of HEPG2 human hepatocellular carcinoma cells in vitro. Initially, IC50 values were determined for each single agent and then for combination of chemotherapy drugs with SK1-II, and their combinatorial effect was finally assessed using CompuSyn software. We showed that SphK inhibition reduces cell viability and sensitizes HEPG2 cells to all chemotherapy drugs investigated in this study. More precisely, the combination of SphK inhibitor with cisplatin resulted mainly in additive or slight antagonistic cytotoxicity. Importantly, the combination of SK1-II with sorafenib exerted mainly additive or slight synergistic cytotoxicity in HEPG2, whereas combinations of SK1-II with either 5-FU or doxorubicin resulted in additive cytotoxicity. Furthermore, apoptotic cell death induced by these chemotherapeutic agents was augmented when the cells were exposed to the combination of drugs and SK1-II at the concentration that specifically produces additive drug-drug effects. Additional studies by Western blot showed differential expression of phospho- Erk1/2 and phospho-p38 in HEPG2 between treatment with single drugs and their combinations with SK1-II. In conclusion, our findings demonstrate that SK1-II enhances response of HEPG2 to drugs included in chemotherapy regimen for HCC probably via modulation of MAPK signalling pathways, and propose that incorporation of SphK inhibition with current chemotherapeutic agents may lay the groundwork for the development of novel treatment strategies that would profoundly improve clinical outcomes for HCC patients.

hepatocellular carcinoma ; sorafenib ; cisplatin ; 5-fluorouracil ; SK1-II

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