The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells

Cancer Cell International

Christina M Annunziata¹  Nancy H Colburn³  Joel Schneider²  Matthew R Young³  Gary T Pauly²  Callee Heywood¹  Lidia Hernandez¹  Ethan Sagher¹ 

[1] Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda 20892, MD, USA;Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick 21702, MD, USA;Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick 21702, MD, USA

关键词: Chemotherapy;    NSC676914;    IKKβ;    NF-κB;    Ovarian cancer;   

Others  :  1121676
DOI  :  10.1186/s12935-014-0075-y

 received in 2014-02-20, accepted in 2014-07-22,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Sagher et al.; licensee BioMed Central Ltd.

【 图 表 】

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