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Background

The small molecule NSC676914A was previously identified as an NF-?B 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-?B luciferase reporter gene were generated.

Methods

Levels of NF-?B activity were assessed by luciferase reporter assays, after stimulation with LPA, LPS, TPA, and TNF?, in the presence or absence of a known NF-?B 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-?B inhibition. The compound did not show predicted patterns of effects on NF-?B activity in either lymphoma, ovarian or HEK293 cell lines. In HEK293 cells, the small molecule inhibited NF-?B when cells were stimulated, while in OVCAR3 cells it only partially inhibited NF-?B. Interestingly, we observed rescue of cell death with ROS inhibition.

Conclusions

The current study suggests that the effect of NSC676914A on NF-?B 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-?B-independent anti-cancer activity in ovarian tumor cells.


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