Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC - PubMed (original) (raw)
doi: 10.1016/j.lungcan.2019.07.006. Epub 2019 Jul 12.
Sam Beard 1, Martin P Barr 2, Kazou Umezawa 3, Susan Heavey 4, Peter Godwin 5, Steven G Gray 2, David Cormican 6, Stephen P Finn 7, Kathy A Gately 2, Anthony M Davies 8, Erik W Thompson 1, Derek J Richard 1, Kenneth J O'Byrne 9, Mark N Adams 10, Anne-Marie Baird 11
Affiliations
- PMID: 31446998
- DOI: 10.1016/j.lungcan.2019.07.006
Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC
Sarah-Louise Ryan et al. Lung Cancer. 2019 Sep.
Abstract
Objectives: 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.
Materials and methods: 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.
Results: 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.
Conclusion: 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.
Keywords: Chemotherapy; Cisplatin; DHMEQ; NF-κB; Non-small cell lung cancer; Resistance.
Copyright © 2019 Elsevier B.V. All rights reserved.
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