Abstract
BackgroundThe 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.MethodsLevels 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.ResultsNSC676914A 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.ConclusionsThe 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.
Highlights
The small molecule NSC676914A was previously identified as an Nuclear factor kappa B (NF-κB) inhibitor in Tetradecanoyl phorbol acetate (TPA)-stimulated HEK293 cells (Mol Can Ther 8:571-581, 2009)
NSC676914 was recently identified as an NF-κB inhibitor in a high-throughput screen of a synthetic library aimed at identifying AP-1 inhibitors [5], and shown to inhibit NF-κB transcriptional activity at low concentrations in TPA-stimulated HEK293
Within the ovarian cancer cell panel, NSC676914A caused 50% or more growth inhibition of 7 ovarian cell lines at concentrations between 1 and 10 μM, the same concentration at which NF-κB was inhibited in HEK293 cells [5]
Summary
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 be seen in ovarian cancer cells, and serve as its mechanism of cytotoxicity. Ovarian cancer is frequently diagnosed in the late stages of the disease, and is the most common cause of death among gynecological cancers in women in the United States. Even as it only accounts for 3% of cancer cases in women, it is the fifth most common cause of death from all cancers [1]. NSC676914 was recently identified as an NF-κB inhibitor in a high-throughput screen of a synthetic library aimed at identifying AP-1 inhibitors [5], and shown to inhibit NF-κB transcriptional activity at low concentrations in TPA-stimulated HEK293
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