title: The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells.
abstract: BACKGROUND
  The small molecule NSC676914A was previously identified as an NF-κB inhibitor in TPA-stimulated HEK293 cells (Mol Can Ther 8:571-581, 2009). We hypothesized that this effect would also be seen in ovarian cancer cells, and serve as its mechanism of cytotoxicity. OVCAR3 and HEK293 cell lines stably containing a NF-κB luciferase reporter gene were generated.
  
  
  METHODS
  Levels of NF-κB activity were assessed by luciferase reporter assays, after stimulation with LPA, LPS, TPA, and TNFα, in the presence or absence of a known NF-κB inhibitor or NSC676914A, and cytotoxicity was measured.
  
  
  RESULTS
  NSC676914A was toxic to both OVCAR3 and HEK293 cells. We also investigated the cytotoxicity of NSC676914A on a panel of lymphoma cell lines with well characterized mutations previously shown to determine sensitivity or resistance to NF-κB inhibition. The compound did not show predicted patterns of effects on NF-κB activity in either lymphoma, ovarian or HEK293 cell lines. In HEK293 cells, the small molecule inhibited NF-κB when cells were stimulated, while in OVCAR3 cells it only partially inhibited NF-κB. Interestingly, we observed rescue of cell death with ROS inhibition.
  
  
  CONCLUSIONS
  The current study suggests that the effect of NSC676914A on NF-κB depends on cell type and the manner in which the pathway is stimulated. Furthermore, as it is similarly toxic to lymphoma, OVCAR3 and HEK293 cells, NSC676914A shows promising NF-κB-independent anti-cancer activity in ovarian tumor cells.
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda 20892, MD, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Sagher
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda 20892, MD, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Hernandez
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda 20892, MD, USA.
authors.forename: Callee
authors.initials: C
authors.lastname: Heywood
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick 21702, MD, USA.
authors.forename: Gary T
authors.initials: GT
authors.lastname: Pauly
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick 21702, MD, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Young
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick 21702, MD, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick 21702, MD, USA.
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Colburn
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda 20892, MD, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
keywords: Chemotherapy; IKKβ; NF-κB; NSC676914; Ovarian cancer