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The effects of combined treatment with epidermal growth factor receptor-tyrosine kinase inhibitor and selective cyclooxygenase-2 inhibitor on lung cancer cells : 폐암세포에서 표피성장인자 수용체-티로신 키나아제 억제제와 선택적인 사이클로옥시게나제-2 억제제의 병합치료 효과
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- Authors
- Advisor
- 한성구
- Major
- 의과대학 의학과
- Issue Date
- 2017-08
- Publisher
- 서울대학교 대학원
- Keywords
- lung cancer ; epidermal growth factor receptor mutation ; epidermal growth factor receptor-tyrosine kinase inhibitor ; selective cyclooxygenase-2 inhibitor
- Description
- 학위논문 (박사)-- 서울대학교 대학원 의과대학 의학과, 2017. 8. 한성구.
- Abstract
- Introduction: To overcome the acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs), various strategies have been explored in preclinical and clinical setting. Cyclooxygenase(COX)-2 inhibitors have been reported to suppress cell growth and to lead to apoptosis of various cancer cells by EGFR down-regulation. In the present study, we assessed whether the combination of celecoxib, a COX-2 inhibitor, and EGFR-TKIs could overcome the acquired resistance in lung cancer cells.
Materials and Methods: The EGFR-mutated lung cancer cell lines(HCC827 and PC-9) and drug-resistant cell lines (HCC827/GR, HCC827/ER, PC-9/GR and PC-9/ER) were used. Celecoxib and COX-2 siRNA were used as COX-2 inhibitor. Reversible EGFR-TKIs, gefitinib and erlotinib, and EGFR siRNA were used as EGFR inhibitor. Western blotting was employed to investigate the expression of proteins involved with EGFR signaling.
Results: Addition of celecoxib treatment enhances sensitivity to EGFR-TKIs in parental HCC827 and PC-9 cells harboring with EGFR activating mutation. Combined celecoxib and gefitinib treatment overcame gefitinib resistance via the inhibition of the phosphorylation of MET, EGFR and Akt in HCC827/GR cells. In HCC827/ER cells, combination treatment with erlotinib and celecoxib inhibited the expression of AXL, p-Akt and Erk. We evaluated the ability of combination treatment with gefitinib or erlotinib, and celecoxib to inhibit the proliferation of PC-9 cells with an EGFR T790M mutation. These combinations showed an additive growth inhibition in PC-9/GR cells and a synergistic growth inhibition in PC-9/ER cells through the suppression of EGFR and Akt activities.
Conclusions: The combination of EGFR-TKIs and celecoxib may be a new strategy to overcome the acquired resistance to EGFR-TKIs in lung cancer.
- Language
- English
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