Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts

Cancer Biol Ther. 2011 Mar 1;11(5):524-34. doi: 10.4161/cbt.11.5.14677. Epub 2011 Mar 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Adamantane / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Benzenesulfonates / pharmacology
  • Benzenesulfonates / therapeutic use*
  • Blotting, Western
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Flow Cytometry
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Lysophospholipids / blood
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Sorafenib
  • Sphingosine / analogs & derivatives
  • Sphingosine / blood
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Lysophospholipids
  • Phenylurea Compounds
  • Pyridines
  • Niacinamide
  • sphingosine 1-phosphate
  • Sorafenib
  • 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Mitogen-Activated Protein Kinases
  • Sphingosine
  • Adamantane