Gemcitabine resistance in a highly metastatic subpopulation of a pulmonary adenocarcinoma cell line resistant to gefitinib

  • Authors:
    • Akira Takemura
    • Akihiko Gemma
    • Masahiko Shibuya
    • Kuniko Matsuda
    • Tetsuya Okano
    • Michiya Nara
    • Rintarou Noro
    • Yuji Minegishi
    • Akinobu Yoshimura
    • Shoji Kudoh
  • View Affiliations

  • Published online on: December 1, 2007     https://doi.org/10.3892/ijo.31.6.1325
  • Pages: 1325-1332
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Abstract

The response rates to combination chemotherapy in metastatic non-small cell lung cancer (NSCLC) cases have been reported to be lower than those to induction chemotherapy in locally advanced cases. To understand the relationship between highly metastatic potential and chemosensitivity, we examined the drug sensitivity of a highly metastatic human lung adenocarcinoma cell subpopulation, PC9/f14, which had been previously established in an experimental metastasis model, to commonly used anti-cancer agents (paclitaxel, SN38, gemcitabine, vindesine, etoposide, cisplatin, and carboplatin) via the 3-(4, 5-dimethylthiazol-2-yl)2, 5-diphenyltetrazolium bromide assay. We found that the PC9/f14 subpopulation, which we previously reported to be resistant to gefitinib, was also resistant to gemcitabine (2',2'-difluoro-2'-deoxy-cytidine), a nucleoside analogue. To clarify the mechanisms of the gemcitabine resistance in this subpopulation, we screened the changes to the protein expression profiles of these cells after exposure to gemcitabine, using a 224-antibody microarray analysis. The exposure to gemcitabine in this subpopulation induced an increase in the expression level of the Bcl-X protein, although this expression remained unchanged in the parent cells. Apoptosis following gemcitabine exposure was depressed in the PC9/f14 subpopulation compared with parent cells, as assessed by flow cytometry and TUNEL assay. In addition, knock-down of Bcl-X by RNA interference methodology induced the recovery of gemcitabine sensitivity in PC9/f14. Phosphorylated Akt, which seems to be involved in the gefitinib resistance of this subpopulation, did not change after gemcitabine exposure. In conclusion, this highly metastatic lung cancer subpopulation had multi-resistant characteristics, to both gemcitabine and gefitinib, which were achieved in different ways, during the process of obtaining its highly metastatic potential. The combination of anti-cancer drugs and inhibition of the molecules related with apoptosis and/or Akt pathway might be beneficial in the treatment of metastatic NSCLC.

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December 2007
Volume 31 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Takemura A, Gemma A, Shibuya M, Matsuda K, Okano T, Nara M, Noro R, Minegishi Y, Yoshimura A, Kudoh S, Kudoh S, et al: Gemcitabine resistance in a highly metastatic subpopulation of a pulmonary adenocarcinoma cell line resistant to gefitinib. Int J Oncol 31: 1325-1332, 2007
APA
Takemura, A., Gemma, A., Shibuya, M., Matsuda, K., Okano, T., Nara, M. ... Kudoh, S. (2007). Gemcitabine resistance in a highly metastatic subpopulation of a pulmonary adenocarcinoma cell line resistant to gefitinib. International Journal of Oncology, 31, 1325-1332. https://doi.org/10.3892/ijo.31.6.1325
MLA
Takemura, A., Gemma, A., Shibuya, M., Matsuda, K., Okano, T., Nara, M., Noro, R., Minegishi, Y., Yoshimura, A., Kudoh, S."Gemcitabine resistance in a highly metastatic subpopulation of a pulmonary adenocarcinoma cell line resistant to gefitinib". International Journal of Oncology 31.6 (2007): 1325-1332.
Chicago
Takemura, A., Gemma, A., Shibuya, M., Matsuda, K., Okano, T., Nara, M., Noro, R., Minegishi, Y., Yoshimura, A., Kudoh, S."Gemcitabine resistance in a highly metastatic subpopulation of a pulmonary adenocarcinoma cell line resistant to gefitinib". International Journal of Oncology 31, no. 6 (2007): 1325-1332. https://doi.org/10.3892/ijo.31.6.1325