TY  - JOUR
JF  - Lung Cancer
UR  - https://doi.org/10.1016/j.lungcan.2019.07.006
N2  - 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-?B, 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-?B small molecule inhibitor, DHMEQ, was also assessed by means of viability assays and western blot analysis. RESULTS: Proteomic analysis identified dysregulated NF-?B responsive targets in CisR cells when compared to PT cells, with increased NF-?B expression identified in four out of the five NSCLC sub-types examined (CisR versus PT). DHMEQ treatment resulted in reduced NF-?B expression in the presence of cisplatin, and re-sensitized CisR cells to the cytotoxic effects of the drug. CONCLUSION: This study identified NF-?B as a potential therapeutic target in cisplatin-resistant NSCLC. Furthermore, inhibition of NF-?B using DHMEQ re-sensitized chemo-resistant cells to cisplatin treatment.
VL  - 135
AV  - public
KW  - Non-small cell lung cancer
KW  -  chemotherapy
KW  -  resistance
KW  -  cisplatin
KW  -  DHMEQ
KW  -  NF-?B
SP  - 217
EP  - 227
TI  - Targeting NF-?B-Mediated Inflammatory Pathways in Cisplatin-Resistant NSCLC
ID  - discovery10078144
Y1  - 2019/09//
A1  - Ryan, S-L
A1  - Beard, S
A1  - Barr, MP
A1  - Umezawa, K
A1  - Heavey, S
A1  - Godwin, P
A1  - Gray, SG
A1  - Cormican, D
A1  - Finn, SP
A1  - Gately, KA
A1  - Davies, AM
A1  - Thompson, EW
A1  - Richard, DJ
A1  - O?Byrne, KJ
A1  - Adams, MN
A1  - Baird, A-M
SN  - 0169-5002
PB  - Elsevier BV
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
ER  -