Antiproliferative effects of gefitinib are associated with suppression of E2F-1 expression and telomerase activity.

BACKGROUND Gefitinib (Iressa, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor. E2F-1 is a critical determinant in cell cycle. Growth signals up-regulate telomerase activity. The effects of gefitinib on E2F-1 and telomerase in A549, H23 and A431 cells were examined. MATERIALS AND METHODS Cell proliferation and cell cycle progression were measured by the WST-1 assay and flow cytometry. The expression of E2F-1 and cyclin-dependent kinase inhibitors was evaluated, and hTERT mRNA expression and telomerase activity were analyzed. RESULTS In the A431 and A549 cells, treatment with gefitinib inhibited cell proliferation and was associated with an increase in G1-phase. In both cell types, gefitinib decreased the expression of E2F-1 mRNA and protein, followed by the suppression of hTERT mRNA and telomerase activity. In the H23 cells, gefitinib did not affect cell proliferation. CONCLUSION The antiproliferative effects of gefitinib may be, at least in part, due to the inhibition of E2F-1 expression and telomerase activity.

[1]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[2]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[3]  M. Ueda,et al.  Inhibition of the epidermal growth factor receptor suppresses telomerase activity in HSC-1 human cutaneous squamous cell carcinoma cells. , 2003, The Journal of investigative dermatology.

[4]  Masahiro Fukuoka,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]. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  G. Giaccone,et al.  Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  A. Abbruzzese,et al.  Critical role of both p27KIP1and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells , 2003, Journal of cellular physiology.

[7]  J. Pietenpol,et al.  Cell-cycle dysregulation and anticancer therapy. , 2003, Trends in pharmacological sciences.

[8]  O. Coqueret,et al.  New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? , 2003, Trends in cell biology.

[9]  S. Murakami,et al.  Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway , 2002, Oncogene.

[10]  A. Gartel,et al.  The Role of the Cyclin-dependent Kinase Inhibitor p 21 in Apoptosis 1 , 2002 .

[11]  M. Kris,et al.  ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  E. Gilson,et al.  Natural and pharmacological regulation of telomerase. , 2002, Nucleic acids research.

[13]  P. Bunn,et al.  ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. , 2002, Seminars in oncology.

[14]  G. Fontanini,et al.  Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  D. Crowe,et al.  Rb and E2F-1 regulate telomerase activity in human cancer cells. , 2001, Biochimica et biophysica acta.

[16]  D. V. Von Hoff,et al.  Effects of androgens on telomerase activity in normal and malignant prostate cells in vitro , 2000, The Prostate.

[17]  G. Tortora,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. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  J. Willey,et al.  Expression measurement of many genes simultaneously by quantitative RT-PCR using standardized mixtures of competitive templates. , 1998, American journal of respiratory cell and molecular biology.

[19]  R. Reddel.  Telomerase and cancer. , 1997, Japanese journal of cancer research : Gann.

[20]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[21]  毎田 佳子.  Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway , 2003 .

[22]  June Corwin,et al.  Telomerase Catalytic Subunit Homologs from Fission Yeast and Human , 1997 .