Targeting Ovarian Cancer and Chemoresistance Through Selective Inhibition of Sphingosine kinase-2 With ABC294640

Anticancer Res. 2013 Sep;33(9):3573-9.

Abstract

ABC294640, a selective inhibitor of sphingosine kinase-2, inhibits the formation of sphingosine 1-phosphate (S1P), a signaling lipid implicated in promoting tumor survival. We investigated the anticancer activity of ABC294640 in two ovarian cancer cell lines, BG-1 and Caov-3. ABC294640 dose-dependently inhibited clonogenic survival and cell viability of both ovarian cancer lines in vitro. Using enzyme-linked immunosorbant assays and western blot detection in chemoresistant Caov-3 cells, treatment with ABC294640 alone also potentiated bcl-2-associated X-protein and caspase-9 transcription levels, although it did not significantly increase apoptotic cell death. Interestingly, ABC294640 administered to Caov-3 ovarian cancer cells in conjunction with paclitaxel induced apoptotic cell death through activation of caspase-9. Induction of apoptosis may mediate the anticancer effect of ABC294640 in ovarian cancer, although its precise antitumor mechanism is unclear. Ultimately, through its inhibition of S1P formation and subsequent effects on critical survival signaling cascades, ABC294640 may prove to be a useful adjunct to help re-sensitize tumors to standard therapy.

Keywords: ABC294640; BG-1; Caov-3 cells; Ovarian cancer; chemoresistance; experimental therapeutics; sphingolipids; sphingosine kinase-2; sphingosine-1-phosphate.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Adamantane / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / pathology
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyridines
  • bcl-2-Associated X Protein
  • 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Adamantane