Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation

Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Toshiyuki Kozuki, Akiko Hisamoto, Hideki Katayama, Nagio Takigawa, Nobukazu Fujimoto, Keiichi Fujiwara, Hiroshi Ueoka, Mitsune Tanimoto

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 μM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild-type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 μM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.

Original languageEnglish
Pages (from-to)313-317
Number of pages5
JournalOncology Reports
Volume17
Issue number2
Publication statusPublished - Feb 2007

Fingerprint

erbB-1 Genes
Non-Small Cell Lung Carcinoma
Mutation
Cell Death
Apoptosis
Cultured Tumor Cells
Malignant Pleural Effusion
G1 Phase Cell Cycle Checkpoints
gefitinib
Cell Line
Neoplasms

Keywords

  • Apoptosis
  • EGFR
  • Gefitinib
  • Non-small cell lung cancer
  • Premature senescence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation. / Hotta, Katsuyuki; Tabata, Masahiro; Kiura, Katsuyuki; Kozuki, Toshiyuki; Hisamoto, Akiko; Katayama, Hideki; Takigawa, Nagio; Fujimoto, Nobukazu; Fujiwara, Keiichi; Ueoka, Hiroshi; Tanimoto, Mitsune.

In: Oncology Reports, Vol. 17, No. 2, 02.2007, p. 313-317.

Research output: Contribution to journalArticle

Hotta, K, Tabata, M, Kiura, K, Kozuki, T, Hisamoto, A, Katayama, H, Takigawa, N, Fujimoto, N, Fujiwara, K, Ueoka, H & Tanimoto, M 2007, 'Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation', Oncology Reports, vol. 17, no. 2, pp. 313-317.
Hotta, Katsuyuki ; Tabata, Masahiro ; Kiura, Katsuyuki ; Kozuki, Toshiyuki ; Hisamoto, Akiko ; Katayama, Hideki ; Takigawa, Nagio ; Fujimoto, Nobukazu ; Fujiwara, Keiichi ; Ueoka, Hiroshi ; Tanimoto, Mitsune. / Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation. In: Oncology Reports. 2007 ; Vol. 17, No. 2. pp. 313-317.
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