The balance between the pro-apoptotic
lipids ceramide and
sphingosine and the pro-survival
lipid sphingosine 1-phosphate (S1P) is termed the "
sphingosine rheostat". Two
isozymes,
sphingosine kinase 1 and 2 (SK1 and SK2), are responsible for phosphorylation of pro-apoptotic
sphingosine to form pro-survival S1P. We have previously reported the antitumor properties of an SK2 selective inhibitor,
ABC294640, alone or in combination with the multikinase inhibitor
sorafenib in mouse models of kidney
carcinoma and pancreatic
adenocarcinoma. Here we evaluated the combined antitumor effects of the aforementioned
drug combination in two mouse models of
hepatocellular carcinoma. Although combining the SK2 inhibitor,
ABC294640, and
sorafenib in vitro only afforded additive
drug-
drug effects, their combined antitumor properties in the mouse model bearing HepG2 cells mirrored effects previously observed in animals bearing kidney
carcinoma and pancreatic
adenocarcinoma cells. Combining
ABC294640 and
sorafenib led to a decrease in the levels of phosphorylated ERK in SK-HEP-1 cells, indicating that the antitumor effect of this
drug combination is likely mediated through a suppression of the MAPK pathway in hepatocellular models. We also measured levels of S1P in the plasma of mice treated with two different doses of
ABC294640 and
sorafenib. We found decreases in the levels of S1P in plasma of mice treated daily with 100 mg/kg of
ABC294640 for 5 weeks, and this decrease was not affected by co-administration of
sorafenib. Taken together, these data support combining
ABC294640 and
sorafenib in clinical trials in HCC patients. Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of
ABC294640 activity.