Sarah-Louise Ryan1, Sam Beard1, Martin P Barr2, Kazou Umezawa3, Susan Heavey4, Peter Godwin5, Steven G Gray2, David Cormican6, Stephen P Finn7, Kathy A Gately2, Anthony M Davies8, Erik W Thompson1, Derek J Richard1, Kenneth J O'Byrne9, Mark N Adams10, Anne-Marie Baird11. 1. The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia. 2. Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland. 3. Department of Molecular Target Medicine, Aichi Medical University, Nagakute, Japan. 4. Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Division of Surgery and Interventional Sciences, University College London, United Kingdom. 5. Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland. 6. Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College Dublin, Dublin, Ireland. 7. Department of Histopathology and Morbid Anatomy, School of Medicine, Trinity College Dublin, Dublin, Ireland; Department of Histopathology, Labmed Directorate, St. James's Hospital, Dublin, Ireland. 8. Vale Life Sciences Pty., Translational Research Institute, Brisbane, Australia. 9. The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia; Princess Alexandra Hospital, Brisbane, Australia. 10. The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia. Electronic address: mn.adams@qut.edu.au. 11. The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia; Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland. Electronic address: bairda@tcd.ie.
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.
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.
Authors: Marcin Michalak; Michał S Lach; Sylwia Borska; Błażej Nowakowski; Kazuo Umezawa; Wiktoria M Suchorska Journal: Am J Cancer Res Date: 2021-12-15 Impact factor: 6.166
Authors: Amila Suraweera; Alex Duff; Mark N Adams; Christian Jekimovs; Pascal H G Duijf; Cheng Liu; Matthew McTaggart; Sam Beard; Kenneth J O'Byrne; Derek J Richard Journal: Br J Cancer Date: 2020-05-22 Impact factor: 7.640