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Article

Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines

  • Authors:
    • Jing Li
    • Yue‑Yin Pan
    • Ying Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Geriatrics, The Third Affiliated Hospital of Anhui Medical University, Hefei 230061, P.R. China, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, P.R. China
  • Pages: 440-446
    |
    Published online on: November 7, 2012
       https://doi.org/10.3892/ol.2012.1017
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Abstract

Sorafenib is a highly selective multi‑targeted agent and has been reported to have potent antitumor effects against various tumors, including human non‑small cell lung cancer (NSCLC). In the present study, we explored the antitumor effect and associated molecular mechanisms of sorafenib against human lung cancer cell lines in vitro. We also investigated the efficacy of concurrent and sequential administration of sorafenib and gemcitabine in epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitor (TKI)‑sensitive and EGFR‑TKI‑resistant NSCLC cell lines. The PC‑9 (EGFR‑TKI‑sensitive, EGFR-mutated) and A549 (EGFR‑TKI‑resistant, K‑Ras-mutated) NSCLC cell lines were treated with sorafenib and gemcitabine, alone, in combination or with different schedules. Cytotoxicity was assessed by MTT assay, cell cycle distribution was analyzed by flow cytometry and alterations in signaling pathways were analyzed by western blotting. We found that sorafenib exhibited dose‑dependent growth inhibition in the EGFR‑TKI‑sensitive and EGFR-TKI‑resistant NSCLC cell lines, and the sequence gemcitabine→sorafenib exhibited the strongest synergism. Sorafenib arrested the cell cycle at G1 phase, whereas gemcitabine caused arrest at S phase. The molecular mechanism of this synergism is that the downstream signaling pathways that were initially activated by gemcitabine exposure were efficiently suppressed by the subsequent exposure to sorafenib. By contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. The results suggest that sorafenib as a single agent exhibits anti‑proliferative effects in vitro in NSCLC cell lines with EGFR and K‑Ras mutations and that the sequential administration of gemcitabine followed by sorafenib is superior to sorafenib followed by gemcitabine and concurrent administration.
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Copy and paste a formatted citation
Spandidos Publications style
Li J, Pan YY and Zhang Y: Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines. Oncol Lett 5: 440-446, 2013.
APA
Li, J., Pan, Y., & Zhang, Y. (2013). Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines. Oncology Letters, 5, 440-446. https://doi.org/10.3892/ol.2012.1017
MLA
Li, J., Pan, Y., Zhang, Y."Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines". Oncology Letters 5.2 (2013): 440-446.
Chicago
Li, J., Pan, Y., Zhang, Y."Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines". Oncology Letters 5, no. 2 (2013): 440-446. https://doi.org/10.3892/ol.2012.1017
Copy and paste a formatted citation
x
Spandidos Publications style
Li J, Pan YY and Zhang Y: Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines. Oncol Lett 5: 440-446, 2013.
APA
Li, J., Pan, Y., & Zhang, Y. (2013). Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines. Oncology Letters, 5, 440-446. https://doi.org/10.3892/ol.2012.1017
MLA
Li, J., Pan, Y., Zhang, Y."Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines". Oncology Letters 5.2 (2013): 440-446.
Chicago
Li, J., Pan, Y., Zhang, Y."Synergistic interaction between sorafenib and gemcitabine in EGFR‑TKI‑sensitive and EGFR‑TKI‑resistant human lung cancer cell lines". Oncology Letters 5, no. 2 (2013): 440-446. https://doi.org/10.3892/ol.2012.1017
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