ZD1839 (IRESSA®) stabilizes p27kip1 and enhances radiosensitivity in cholangiocarcinoma cell lines

Shinichi Yabuuchi, Y. U. Katayose, O. D.A. Akira, Masamichi Mizuma, Satoru Shirasou, Tsuyoshi Sasaki, Kuniharu Yamamoto, Masaya Oikawa, Toshiki Rikiyama, Tohru Onogawa, Hiroshi Yoshida, Hideo Ohtuska, Fuyuhiko Motoi, Shinichi Egawa, Michiaki Unno

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

The prognosis of cholangiocarcinoma patients is extremely poor despite the aggressive multidisciplinary cancer therapies that have been used clinically (1). Recently, molecular target therapy has attracted attention. Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) is a promising target for anticancer therapy. ZDI839 (IRESSA®) is an orally active, selective inhibitor ofEGFR- TK. This study examined the effects of ZD1839 in TFK-1 and HuCCTl, the human cholangiocarcinoma cell lines that express EGFR. Somatic mutations in the TK domain of the EGFR gene are associated with the sensitivity of lung cancers to ZD1839 (2). In the analysis of the EGFR sequence, no mutations were found in TFK-1 and HuCCTl. The TFK-1 and HuCCTl cells showed almost the same sensitivity to ZD1839. It is shown that ZD1839 induced apoptotic cell death of TFK-1 cells as indicated by apoptotic morphological changes and an enhancement of TUNEL-positive cells. ZD1839 produced a dose-dependent inhibition of cellular proliferation in TFK-1. Cell cycle analysis demonstrated that ZD1839 induces Gl arrest. Moreover, concurrent evaluation of the expression of p27kip1 protein and Jun activating domain-binding protein 1 (Jabl) with ZD1839 by Western blotting analysis was performed. It was found that ZD1839 activity causes an increase of p27kip1 stability that correlates with Jabl down-regulation. Thus, ZD1839 affects key cellular.

Original languageEnglish
Pages (from-to)1169-1180
Number of pages12
JournalAnticancer research
Volume29
Issue number4
Publication statusPublished - 2009 Apr

Keywords

  • Cholangiocarcinoma
  • Jabl
  • P27
  • Radiation
  • ZD1839

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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