ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma

Fuminori Teranishi, Shunsuke Kagawa, Takanori Watanabe, Yasuhisa Tango, Takeshi Kawashima, Tatsuo Umeoka, Masahiko Nisizaki, Noriaki Tanaka, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at G0-G1 phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients.

Original languageEnglish
Pages (from-to)4069-4075
Number of pages7
JournalFEBS Letters
Volume579
Issue number19
DOIs
Publication statusPublished - Aug 1 2005

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TNF-Related Apoptosis-Inducing Ligand
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Apoptosis
Ligands
Esophageal Neoplasms
Squamous Cell Neoplasms
Neoplasms
Phosphorylation
Esophageal Squamous Cell Carcinoma
gefitinib
Epithelial Cells
Cells
Cell signaling
Cell Line
Cell Cycle Resting Phase
Caspase 9
Cell proliferation
G1 Phase
Cell growth

Keywords

  • Akt
  • Epidermal growth factor receptor
  • Esophageal squamous cell cancer
  • Tumor necrosis factor-related apoptosis inducing ligand
  • ZD1839

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma. / Teranishi, Fuminori; Kagawa, Shunsuke; Watanabe, Takanori; Tango, Yasuhisa; Kawashima, Takeshi; Umeoka, Tatsuo; Nisizaki, Masahiko; Tanaka, Noriaki; Fujiwara, Toshiyoshi.

In: FEBS Letters, Vol. 579, No. 19, 01.08.2005, p. 4069-4075.

Research output: Contribution to journalArticle

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