Lidocaine alleviates cytotoxicity-resistance in lung cancer A549/DDP cells via down-regulation of miR-21

  • Qing Yang
  • Zhi Zhang
  • Haixia XuEmail author
  • Chuangen MaEmail author


Lidocaine (Lido) is a commonly used local anesthetic, which has been reported in various types of cells. However, the effects of Lido on lung cancer cells remain not understood. The study aimed to investigate the underlying mechanisms of Lido in the cisplatin resistance of A549/DDP cells. Different concentrations of cisplatin (0–320 µM) were used to stimulate A549 and A549/DDP cells, and cell viability and apoptosis were examined. To investigate the effect of Lido on A549/DDP cells, the optimum concentration of Lido was selected to treat A549/DDP cells, and cell viability, apoptosis, migration and invasion were then detected. The relative expression of miR-21 in A549/DDP cells or in Lido-treated A549/DDP cells was analyzed by RT-qPCR. MiR-21 mimic, inhibitor and its control were transfected into A549/DDP cells to explore the regulatory effect of miR-21 on the cisplatin resistance in A549 or A549/DDP cells. The effects of miR-21 on PTEN/PI3K/AKT and PDCD4/JNK pathways were detected by western blot. The cisplatin resistance of A549/DDP cells was higher than that of A549 cells. Lido significantly suppressed cell viability, induced apoptosis, and inhibited cell migration and invasion in A549/DDP cells. Additionally, miR-21 expression in A549/DDP was higher than that in A549 cells, and Lido significantly down-regulated miR-21 expression in A549/DDP cells. MmiR-21 inhibition exhibited the same effects as Lido on the cisplatin resistance of A549/DDP cells. Further, miR-21 suppression regulated PTEN/PI3K/AKT and PDCD4/JNK pathways in A549/DDP cells. These findings indicated that Lido alleviated the cytotoxicity resistance of A549/DDP cells via down-regulation of miR-21.

Graphical abstract


Lung cancer Lidocaine Cisplatin MicroRNA-21 PTEN/PI3K/AKT PDCD4/JNK 



This work was supported by Kaifeng City Social Development Plan Project (Grant No: 1503113).


  1. 1.
    Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S, Brahmer JR, Ellis PM, Gajra A, Rackear N, Schiller JH (2017) Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 33:832–837Google Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cheng TD, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME (2016) The international epidemiology of lung cancer: latest trends, disparities, and tumor characteristics. J Thorac Oncol 11:1653–1671CrossRefGoogle Scholar
  4. 4.
    Thun MJ, Hannan LM, Adams-Campbell LL, Boffetta P, Buring JE, Feskanich D, Flanders WD, Jee SH, Katanoda K, Kolonel LN, Lee IM, Marugame T, Palmer JR, Riboli E, Sobue T, Avila-Tang E, Wilkens LR, Samet JM (2008) Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS Med 5:e185. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ebbinghaus S (2015) Lung cancer treatment. Clin Pharm 3:109–114Google Scholar
  6. 6.
    Simone CB 2nd, Jones JA (2013) Palliative care for patients with locally advanced and metastatic non-small cell lung cancer. Ann Palliat Med 2:178–188. CrossRefPubMedGoogle Scholar
  7. 7.
    Xue D, Abernethy AP (2010) Management of dyspnea in advanced lung cancer: recent data and emerging concepts. Curr Opin Support Palliat Care 4:85–91. CrossRefPubMedGoogle Scholar
  8. 8.
    Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833. CrossRefPubMedGoogle Scholar
  9. 9.
    Liu MY, Li XQ, Gao TH, Cui Y, Ma N, Zhou Y, Zhang GJ (2016) Elevated HOTAIR expression associated with cisplatin resistance in non-small cell lung cancer patients. J Thorac Dis 8:3314–3322. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bang SU, Kim DJ, Bae JH, Chung K, Kim Y (2016) Minimum effective local anesthetic volume for surgical anesthesia by subparaneural, ultrasound-guided popliteal sciatic nerve block: a prospective dose-finding study. Medicine 95:e4652. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chang YC, Hsu YC, Liu CL, Huang SY, Hu MC, Cheng SP (2014) Local anesthetics induce apoptosis in human thyroid cancer cells through the mitogen-activated protein kinase pathway. PLoS ONE 9:e89563CrossRefGoogle Scholar
  12. 12.
    Chang YC, Liu CL, Chen MJ, Hsu YW, Chen SN, Lin CH, Chen CM, Yang FM, Hu MC (2014) Local anesthetics induce apoptosis in human breast tumor cells. Anesth Analg 118:116–124CrossRefGoogle Scholar
  13. 13.
    Chan SM, Lin BF, Wong CS, Chuang WT, Chou YT, Wu ZF (2017) Levobuipivacaine-induced dissemination of A549 lung cancer cells. Sci Rep 7:8646. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Uzun S, Yuce Y, Erden A, Aypar U (2014) Impact of perioperative lidocaine infusion and bis monitorization on remifentanil dosage in hypotensive anesthesia. Eur Rev Med Pharmacol Sci 18:559–565PubMedGoogle Scholar
  15. 15.
    Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H (2009) The effect of perioperative intravenous lidocaine on postoperative pain and immune function. Anesth Analg 109:1464–1469. CrossRefPubMedGoogle Scholar
  16. 16.
    Baochun FU, Wang T, Xinzhou YU, Anesthesiology DO (2017) Effects of lidocaine epidural block combined with general anesthesia on postoperative related indexes of lung cancer patients. China Pharm 28:1626–1629Google Scholar
  17. 17.
    Nordentoft I, Birkenkamp-Demtroder K, Agerbaek M, Theodorescu D, Ostenfeld MS, Hartmann A, Borre M, Orntoft TF, Dyrskjot L (2012) miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer. BMC Med Genom 5:40. CrossRefGoogle Scholar
  18. 18.
    Liu XG, Zhu WY, Huang YY, Ma LN, Zhou SQ, Wang YK, Zeng F, Zhou JH, Zhang YK (2012) High expression of serum miR-21 and tumor miR-200c associated with poor prognosis in patients with lung cancer. Med Oncol 29:618–626. CrossRefPubMedGoogle Scholar
  19. 19.
    Liu ZL, Wang H, Liu J, Wang ZX (2013) MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem 372:35–45. CrossRefPubMedGoogle Scholar
  20. 20.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408CrossRefGoogle Scholar
  21. 21.
    Ryu SY, Kim K, Lee WS, Kwon HC, Lee KH, Kim CM, Kang S-B (2009) Synergistic growth inhibition by combination of adenovirus mediated p53 transfer and cisplatin in ovarian cancer cell lines. J Gynecol Oncol 20:48–54. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Festuccia C, Gravina GL, D’Alessandro AM, Muzi P, Millimaggi D, Dolo V, Ricevuto E, Vicentini C, Bologna M (2009) Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models. Endocr Relat Cancer 16:401–413. CrossRefPubMedGoogle Scholar
  23. 23.
    Li D, Zhang Y, Xie Y, Xiang J, Zhu Y, Yang J (2013) Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer. Cancer Gene Ther 20:251–259CrossRefGoogle Scholar
  24. 24.
    Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M (2007) Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol 18:317–323. CrossRefPubMedGoogle Scholar
  25. 25.
    Fennell DA, Summers Y, Cadranel J, Benepal T, Christoph DC, Lal R, Das M, Maxwell F, Visseren-Grul C, Ferry D (2016) Cisplatin in the modern era: the backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat Rev 44:42–50. CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang K, Wang X, Wang H (2014) Effect and mechanism of Src tyrosine kinase inhibitor sunitinib on the drug-resistance reversal of human A549/DDP cisplatin-resistant lung cancer cell line. Mol Med Rep 10:2065–2072. CrossRefPubMedGoogle Scholar
  27. 27.
    Chaki T, Sugino S, Janicki PK, Ishioka Y, Hatakeyama Y, Hayase T, Kaneuchi-Yamashita M, Kohri N, Yamakage M (2016) Efficacy and safety of a lidocaine and ropivacaine mixture for scalp nerve block and local infiltration anesthesia in patients undergoing awake craniotomy. J Neurosurg Anesthesiol 28:1–5. CrossRefPubMedGoogle Scholar
  28. 28.
    Li K, Yang J, Han X (2014) Lidocaine sensitizes the cytotoxicity of cisplatin in breast cancer cells via up-regulation of RARβ2 and RASSF1A demethylation. Int J Mol Sci 15:23519–23536CrossRefGoogle Scholar
  29. 29.
    Xing W, Chen DT, Pan JH, Chen YH, Yan Y, Li Q, Xue RF, Yuan YF, Zeng WA (2017) Lidocaine induces apoptosis and suppresses tumor growth in human hepatocellular carcinoma cells in vitro and in a xenograft model in vivo. Anesthesiology 126:868–881. CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang L, Hu R, Cheng Y, Wu X, Xi S, Sun Y, Jiang H (2017) Lidocaine inhibits the proliferation of lung cancer by regulating the expression of GOLT1A. Cell Prolif 50.
  31. 31.
    Wang HW, Wang LY, Jiang L, Tian SM, Zhong TD, Fang XM (2016) Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer. J Thorac Dis 8:2748–2757. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang Q, Zhong M, Liu W, Li J, Huang J, Zheng L (2011) Alterations of microRNAs in cisplatin-resistant human non-small cell lung cancer cells (A549/DDP). Exp Lung Res 37:427–434. CrossRefPubMedGoogle Scholar
  33. 33.
    Ma Y, Li X, Cheng S, Wei W, Li Y (2015) MicroRNA-106a confers cisplatin resistance in non-small cell lung cancer A549 cells by targeting adenosine triphosphatase-binding cassette A1. Mol Med Rep 11:625–632. CrossRefPubMedGoogle Scholar
  34. 34.
    Xu L, Huang Y, Chen D, He J, Zhu W, Zhang Y, Liu X (2014) Down-regulation of miR-21 increases cisplatin sensitivity of non-small-cell lung cancer. Cancer Genet 207:214–220. CrossRefPubMedGoogle Scholar
  35. 35.
    Tian M, Wang Y, Miao L, Ding J, Zhang D, Cai H (2014) Effects of miR-21 inhibition on A549/DDP cisplatin resistant cell proliferation and apoptosis in non-small cell lung cancer. J Nanjing Med Univ 30:20Google Scholar
  36. 36.
    Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH (2010) MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta 411:846–852CrossRefGoogle Scholar
  37. 37.
    Yang Z, Fang S, Di Y, Ying W, Tan Y, Gu W (2015) Modulation of NF-κB/miR-21/PTEN pathway sensitizes non-small cell lung cancer to cisplatin. PLoS ONE 10:e0121547CrossRefGoogle Scholar
  38. 38.
    Zhang Y, Bao C, Mu Q, Chen J, Wang J, Mi Y, Sayari AJ, Chen Y, Guo M (2016) Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells. Neoplasma 63:362–370. CrossRefPubMedGoogle Scholar
  39. 39.
    Ning FL, Wang F, Li ML, Yu ZS, Hao YZ, Chen SS (2014) MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4. Diagn Pathol 9:143. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Fu Y, Han X, Li Y (2013) Inhibition of the JNK pathway down-regulates lung-resistance protein and enhances the chemosensitivity of A549 cells to cisplatin. Chin J Clin Oncol 40:1518–1522Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyHuaihe Hospital of Henan UniversityKaifengChina

Personalised recommendations