Details

Autor(en) / Beteiligte

• Ryan, Sarah-Louise
• Beard, Sam
• Barr, Martin P.
• Umezawa, Kazou
• Heavey, Susan
• Godwin, Peter
• Gray, Steven G.
• Cormican, David
• Finn, Stephen P.
• Gately, Kathy A.
• Davies, Anthony M.
• Thompson, Erik W.
• Richard, Derek J.
• O’Byrne, Kenneth J.
• Adams, Mark N.
• Baird, Anne-Marie

Titel

Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC

Ist Teil von

• Lung cancer (Amsterdam, Netherlands), 2019-09, Vol.135, p.217-227

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• •Altered NF-ĸB expression was evident in cisplatin-resistant versus cisplatin-sensitive NSCLC cells.•The NF-κB inhibitor, DHMEQ, counteracted a cisplatin-mediated increase in NF-κB expression.•DHMEQ treatment enhanced the sensitivity of cisplatin-resistant NSCLC cells to cisplatin in vitro. The majority of patients with non-small cell lung cancer (NSCLC) present with advanced stage disease, at which time chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with platinum-based regimens will eventually develop resistance, with others presenting with intrinsic resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project was to determine the role of inflammatory mediators in cisplatin-resistance in NSCLC. Inflammatory mediator, NF-κB, and its associated pathways were investigated in an isogenic model of cisplatin-resistant NSCLC using age-matched parental (PT) and corresponding cisplatin-resistant (CisR) sublines. Pathways were assessed using mass spectrometry, western blot analysis and qRT-PCR. The cisplatin sensitizing potential of an NF-κB small molecule inhibitor, DHMEQ, was also assessed by means of viability assays and western blot analysis. Proteomic analysis identified dysregulated NF-κB responsive targets in CisR cells when compared to PT cells, with increased NF-κB expression identified in four out of the five NSCLC sub-types examined (CisR versus PT). DHMEQ treatment resulted in reduced NF-κB expression in the presence of cisplatin, and re-sensitized CisR cells to the cytotoxic effects of the drug. This study identified NF-ĸB as a potential therapeutic target in cisplatin-resistant NSCLC. Furthermore, inhibition of NF-ĸB using DHMEQ re-sensitized chemo-resistant cells to cisplatin treatment.