Ryan, S-L;
Beard, S;
Barr, MP;
Umezawa, K;
Heavey, S;
Godwin, P;
Gray, SG;
... Baird, A-M; + view all
(2019)
Targeting NF-κB-Mediated Inflammatory Pathways in Cisplatin-Resistant NSCLC.
Lung Cancer
, 135
pp. 217-227.
10.1016/j.lungcan.2019.07.006.
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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.
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