Inhibitory effect and mechanism of gefitinib combined with metformin on EGFR-TKI intrinsic resistant NSCLC H1975 cells

Yonghong Pan; Lin Jiao; Caiyu Lin; Conghua Lu; Yubo Wang; Hengyi Chen; Li Li; Yong He

doi:10.16016/j.1000-5404.201610137

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Inhibitory effect and mechanism of gefitinib combined with metformin on EGFR-TKI intrinsic resistant NSCLC H1975 cells

更新时间：2026-01-09

- Inhibitory effect and mechanism of gefitinib combined with metformin on EGFR-TKI intrinsic resistant NSCLC H1975 cells
- Journal of Third Military Medical University Vol. 39, Issue 7, Pages: 668-674(2017)
- 作者机构：
- 作者简介：
- 基金信息：
- DOI：10.16016/j.1000-5404.201610137
  CLC：
- Received：23 October 2016，
  
  Published：2017-07
- 稿件说明：
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Yonghong Pan, Lin Jiao, Caiyu Lin, et al. Inhibitory effect and mechanism of gefitinib combined with metformin on EGFR-TKI intrinsic resistant NSCLC H1975 cells[J]. Journal of Third Military Medical University, 2017, 39(7): 668-674.
DOI：

Yonghong Pan, Lin Jiao, Caiyu Lin, et al. Inhibitory effect and mechanism of gefitinib combined with metformin on EGFR-TKI intrinsic resistant NSCLC H1975 cells[J]. Journal of Third Military Medical University, 2017, 39(7): 668-674. DOI： 10.16016/j.1000-5404.201610137.

摘要

Abstract

Objective

To investigate the synergistic inhibitory effect of gefitinib combined with metformin on non-small cell lung cancer cell line H1975 with intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs)

and explore the underlying mechanism.

Methods

After H1975 cells were treated by gefitinib or/and metformin

MTT assay and colony formation assay were used to observe the proliferation of the cells. Cell invasion was tested by matrigel-coated Transwell chamber assay

and migration ability was measured by wound healing assay. TUNEL assay was employed to observe apoptotic rate. The protein levels of apoptosis and epithelial to mesenchymal transition (EMT) related proteins were assayed by immunofluorescence assay and Western blotting.

Results

Gefitinib combined with metformin showed more obviously synergistic inhibitory effect on the proliferation

invasion and migration in H1975 cells than gefitinib alone (

0.05). As compared to the untreated control cells

gefitinib and metformin alone promoted the cell apoptosis. Their combination induced an even higher apoptotic rate in H1975 cells (

0.05)

down-regulated anti-apoptotic proteins Bcl-xl and Mcl-1

up-regulated pro-apoptotic protein Bax

enhanced the EMT reversion

decreased the expression levels of mesenchymal markers

Vimentin

N-cadherin

Slug

Snail while increased the epithelial marker E-cadherin.

Conclusion

Combination of gefitinib and metformin remarkably inhibits the growth

invasion and migration and induces the apoptosis in inherent EGFR-TKIs resistant H1975 cells. The potential mechanism for antitumor might be due to their activation on mitochondrial apoptosis pathway and EMT reversal.

关键词

Keywords

references

Herbst R S Heymach J V Lippman S M Lung cancer N Engl J Med 2008 359 13 1367 1380 10.1056/NEJMra0802714 Herbst R S, Heymach J V, Lippman S M. Lung cancer[J]. N Engl J Med, 2008, 359(13): 1367-1380. DOI: 10.1056/NEJMra0802714

Mok T S Wu Y L Thongprasert S Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 2009 361 10 947 957 10.1056/NEJMoa0810699 Mok T S, Wu Y L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma[J]. N Engl J Med, 2009, 361(10): 947-957. DOI: 10.1056/NEJMoa 0810699

Rosell R Carcereny E Gervais R Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial Lancet Oncol 2012 13 3 239 246 10.1016/S1470-2045(11)70393-X Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial[J]. Lancet Oncol, 2012, 13(3): 239-246. DOI: 10.1016/S1470-2045(11)70393-X

Maemondo M Inoue A Kobayashi K Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 2010 362 25 2380 2388 10.1056/NEJMoa0909530 Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J]. N Engl J Med, 2010, 362(25): 2380-2388. DOI: 10.1056/NEJMoa0909530

Li L Han R Xiao H Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal Clin Cancer Res 2014 20 10 2714 2726 10.1158/1078-0432.CCR-13-2613 Li L, Han R, Xiao H, et al. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal[J]. Clin Cancer Res, 2014, 20(10): 2714-2726. DOI: 10.1158/1078-0432.CCR-13-2613

Wang J Wang B Chu H Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations Onco Targets Ther 2016 9 3711 3726 10.2147/ott.s106399 Wang J, Wang B, Chu H, et al.Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations[J].Onco Targets Ther, 2016, 9: 3711-3726. DOI: 10.2147/ott.s106399

Su K Y Chen H Y Li K C Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer J Clin Oncol 2012 30 4 433 440 10.1200/JCO.2011.38.3224 Su K Y, Chen H Y, Li K C, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer[J]. J Clin Oncol, 2012, 30(4): 433-440. DOI: 10.1200/JCO.2011.38.3224

Miller V A Hirsh V Cadranel J Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial Lancet Oncol 2012 13 5 528 538 10.1016/S1470-2045(12)70087-6 Miller V A, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial[J]. Lancet Oncol, 2012, 13(5): 528-538. DOI: 10.1016/S1470-2045(12)70087-6

Thress K S Paweletz C P Felip E Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M Nat Med 2015 21 6 560 562 10.1038/nm.3854 Thress K S, Paweletz C P, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M[J]. Nat Med, 2015, 21(6): 560-562. DOI: 10.1038/nm.3854

Sequist L V Soria J C Goldman J W Rociletinib in EGFR-mutated non-small-cell lung cancer N Engl J Med 2015 372 18 1700 1709 10.1056/NEJMoa1413654 Sequist L V, Soria J C, Goldman J W, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer[J]. N Engl J Med, 2015, 372(18): 1700-1709. DOI: 10.1056/NEJMoa1413654

Leone A Di Gennaro E Bruzzese F New perspective for an old antidiabetic drug: metformin as anticancer agent Cancer Treat Res 2014 159 355 376 10.1007/978-3-642-38007-5_21 Leone A, Di Gennaro E, Bruzzese F, et al. New perspective for an old antidiabetic drug: metformin as anticancer agent[J]. Cancer Treat Res, 2014, 159: 355-376. DOI: 10.1007/978-3-642-38007-5_21

Chen H Yao W Chu Q Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes Cancer Lett 2015 369 1 97 102 10.1016/j.canlet.2015.08.024 Chen H, Yao W, Chu Q, et al. Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes[J]. Cancer Lett, 2015, 369(1): 97-102. DOI: 10.1016/j.canlet.2015.08.024

Park K S Raffeld M Moon Y W CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance J Clin Invest 2014 124 7 3003 3015 10.1172/JCI73048 Park K S, Raffeld M, Moon Y W, et al. CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance[J]. J Clin Invest, 2014, 124(7): 3003-3015. DOI: 10.1172/JCI73048

Liu Z Qi S Zhao X Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells Oncotarget 2016 7 16 21315 21331 10.18632/oncotarget.7040 Liu Z, Qi S, Zhao X, et al. Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells[J]. Oncotarget, 2016, 7(16): 21315-21331. DOI: 10.18632/oncotarget.7040

Zhang R Zhang P Wang H Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+) CD117(+) ovarian cancer stem cells Stem Cell Res Ther 2015 6 262 10.1186/s13287-015-0249-0 Zhang R, Zhang P, Wang H, et al.Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+) CD117(+) ovarian cancer stem cells[J].Stem Cell Res Ther, 2015, 6: 262.DOI: 10.1186/s13287-015-0249-0

Tania M Khan M A Fu J Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer Tumour Biol 2014 35 8 7335 7342 10.1007/s13277-014-2163-y Tania M, Khan M A, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer[J]. Tumour Biol, 2014, 35(8): 7335-7342. DOI: 10.1007/s13277-014-2163-y

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