The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells
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 lin...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198909/ https://www.ncbi.nlm.nih.gov/pubmed/25324692 http://dx.doi.org/10.1186/s12935-014-0075-y |
_version_ | 1782339816391704576 |
---|---|
author | Sagher, Ethan Hernandez, Lidia Heywood, Callee Pauly, Gary T Young, Matthew R Schneider, Joel Colburn, Nancy H Annunziata, Christina M |
author_facet | Sagher, Ethan Hernandez, Lidia Heywood, Callee Pauly, Gary T Young, Matthew R Schneider, Joel Colburn, Nancy H Annunziata, Christina M |
author_sort | Sagher, Ethan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4198909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41989092014-10-17 The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells Sagher, Ethan Hernandez, Lidia Heywood, Callee Pauly, Gary T Young, Matthew R Schneider, Joel Colburn, Nancy H Annunziata, Christina M Cancer Cell Int Primary Research 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. BioMed Central 2014-08-12 /pmc/articles/PMC4198909/ /pubmed/25324692 http://dx.doi.org/10.1186/s12935-014-0075-y Text en Copyright © 2014 Sagher et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Primary Research Sagher, Ethan Hernandez, Lidia Heywood, Callee Pauly, Gary T Young, Matthew R Schneider, Joel Colburn, Nancy H Annunziata, Christina M The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells |
title | The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells |
title_full | The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells |
title_fullStr | The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells |
title_full_unstemmed | The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells |
title_short | The small molecule NSC676914A is cytotoxic and differentially affects NFκB signaling in ovarian cancer cells and HEK293 cells |
title_sort | small molecule nsc676914a is cytotoxic and differentially affects nfκb signaling in ovarian cancer cells and hek293 cells |
topic | Primary Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198909/ https://www.ncbi.nlm.nih.gov/pubmed/25324692 http://dx.doi.org/10.1186/s12935-014-0075-y |
work_keys_str_mv | AT sagherethan thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT hernandezlidia thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT heywoodcallee thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT paulygaryt thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT youngmatthewr thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT schneiderjoel thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT colburnnancyh thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT annunziatachristinam thesmallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT sagherethan smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT hernandezlidia smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT heywoodcallee smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT paulygaryt smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT youngmatthewr smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT schneiderjoel smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT colburnnancyh smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells AT annunziatachristinam smallmoleculensc676914aiscytotoxicanddifferentiallyaffectsnfkbsignalinginovariancancercellsandhek293cells |