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Article

Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells

  • Authors:
    • Min Wu
    • Yuan Yuan
    • Yue‑Yin Pan
    • Ying Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Geriatrics, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P.R. China, The Central Laboratory of Binhu Hospital, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P.R. China, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
  • Pages: 2417-2422
    |
    Published online on: March 28, 2014
       https://doi.org/10.3892/mmr.2014.2082
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Abstract

In a number of large clinical studies, concurrent administration of the epidermal growth factor receptor‑tyrosine kinase inhibitor (EGFR‑TKI) with cytotoxic chemotherapy has failed to improve the survival rate in unselected patients with advanced non‑small cell lung cancer (NSCLC). The purpose of the current study was to investigate the antitumor effects of gefitinib in combination with docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human lung cancer cell lines and the associated molecular mechanisms. EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines were exposed to gefitinib or docetaxel alone, or in combination. Cell viability was assessed using the MTT assay. Cell cycle distribution and apoptosis were measured by flow cytometry and alterations in signaling pathways were examined by immunoblotting. The cytotoxic interaction between docetaxel and gefitinib was determined by combination index (CI) analysis. Coadministration of gefitinib and docetaxel was observed to result in superior inhibition of tumor cell proliferation, however, increased rates of apoptosis were only observed in EGFR‑TKI‑sensitive cells, whereas, antagonistic activity was observed in the EGFR‑TKI‑resistant cell lines. Gefitinib arrested the cell cycle at the G1 phase, whereas docetaxel arrested the cell cycle at the S phase. In addition, in cells exhibiting a synergistic interaction between gefitinib and docetaxel, an increase in p‑EGFR and p‑AKT was observed following chemotherapy exposure. By contrast, in cells exhibiting no change or a decrease in p‑EGFR and p‑AKT following docetaxel treatment, an antagonistic interaction between the two agents was observed. In conclusion, the combination of docetaxel and gefitinib generated synergistic effects in EGFR‑TKI‑sensitive cells and antagonistic effects in EGFR‑TKI‑primary and acquired resistant cells, suggesting that EGFR‑TKIs, combined with docetaxel, may be beneficial to NSCLC patients with EGFR mutations. The results also indicate that the interactions between gefitinib and docetaxel may be associated with the effect of docetaxel on EGFR phosphorylation.
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1 

Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar

2 

Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 346:92–98. 2002. View Article : Google Scholar

3 

Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2:e172005. View Article : Google Scholar : PubMed/NCBI

6 

Jackman D, Pao W, Riely GJ, et al: Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 28:357–360. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar

8 

Gloeckler Ries LA, Reichman ME, Lewis DR, Hankey BF and Edwards BK: Cancer survival and incidence from the Surveillance, Epidemiology, and End Results (SEER) program. Oncologist. 8:541–552. 2003.

9 

Schiff PB, Fant J and Horwitz SB: Promotion of microtubule assembly in vitro by taxol. Nature. 277:665–667. 1979. View Article : Google Scholar : PubMed/NCBI

10 

Gligorov J and Lotz JP: Preclinical pharmacology of the taxanes: implications of the differences. Oncologist. 9(Suppl 2): 3–8. 2004. View Article : Google Scholar : PubMed/NCBI

11 

Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 21:2237–2246. 2003.

12 

Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 290:2149–2158. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 6:2053–2063. 2000.

14 

Sirotnak FM, Zakowski MF, Miller VA, Scher HI and Kris MG: Efficacy of cytotoxic agents against human tumor xeno-grafts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 6:4885–4892. 2000.PubMed/NCBI

15 

Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 2. J Clin Oncol. 22:785–794. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 1. J Clin Oncol. 22:777–784. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Gandara D, Narayan S, Lara PN Jr, et al: Integration of novel therapeutics into combined modality therapy of locally advanced non-small cell lung cancer. Clin Cancer Res. 11:5057s–5062s. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Gandara DR and Gumerlock PH: Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: case closed or is the jury still out? J Clin Oncol. 23:5856–5858. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI

20 

Magné N, Fischel JL, Dubreuil A, et al: Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer. Br J Cancer. 86:819–827. 2002.

21 

Xu JM, Azzariti A, Colucci G and Paradiso A: The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines. Cancer Chemother Pharmacol. 52:442–448. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Higgins B, Kolinsky K, Smith M, et al: Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. Anticancer Drugs. 15:503–512. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 23:5892–5929. 2005. View Article : Google Scholar

24 

Gatzemeier U, Pluzanska A, Szczesna A, et al: Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 25:1545–1552. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Cheng H, An SJ, Zhang XC, et al: In vitro sequence-dependent synergism between paclitaxel and gefitinib in human lung cancer cell lines. Cancer Chemother Pharmacol. 67:637–646. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Davies AM, Ho C, Lara PN Jr, Mack P, Gumerlock PH and Gandara DR: Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer. Clin Lung Cancer. 7:385–388. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Li T, Ling YH, Goldman ID and Perez-Soler R: Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res. 13:3413–3422. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M and Lord JM: Serine/threonine protein kinases and apoptosis. Exp Cell Res. 256:34–41. 2000. View Article : Google Scholar : PubMed/NCBI

29 

Pan F, Tian J, Zhang X, et al: Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. J Cancer Res Clin Oncol. 137:1397–1408. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Van Schaeybroeck S, Karaiskou-McCaul A, Kelly D, et al: Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res. 11:7480–7489. 2005.

31 

Van Schaeybroeck S, Kyula J, Kelly DM, et al: Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cells. Mol Cancer Ther. 5:1154–1165. 2006.

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Copy and paste a formatted citation
Spandidos Publications style
Wu M, Yuan Y, Pan YY and Zhang Y: Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells. Mol Med Rep 9: 2417-2422, 2014.
APA
Wu, M., Yuan, Y., Pan, Y., & Zhang, Y. (2014). Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells. Molecular Medicine Reports, 9, 2417-2422. https://doi.org/10.3892/mmr.2014.2082
MLA
Wu, M., Yuan, Y., Pan, Y., Zhang, Y."Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells". Molecular Medicine Reports 9.6 (2014): 2417-2422.
Chicago
Wu, M., Yuan, Y., Pan, Y., Zhang, Y."Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells". Molecular Medicine Reports 9, no. 6 (2014): 2417-2422. https://doi.org/10.3892/mmr.2014.2082
Copy and paste a formatted citation
x
Spandidos Publications style
Wu M, Yuan Y, Pan YY and Zhang Y: Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells. Mol Med Rep 9: 2417-2422, 2014.
APA
Wu, M., Yuan, Y., Pan, Y., & Zhang, Y. (2014). Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells. Molecular Medicine Reports, 9, 2417-2422. https://doi.org/10.3892/mmr.2014.2082
MLA
Wu, M., Yuan, Y., Pan, Y., Zhang, Y."Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells". Molecular Medicine Reports 9.6 (2014): 2417-2422.
Chicago
Wu, M., Yuan, Y., Pan, Y., Zhang, Y."Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR‑TKI‑sensitive, primary resistant and acquired resistant human non‑small cell lung cancer cells". Molecular Medicine Reports 9, no. 6 (2014): 2417-2422. https://doi.org/10.3892/mmr.2014.2082
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