ZD1839 (IRESSA) stabilizes p27Kip1 and enhances radiosensitivity in cholangiocarcinoma cell lines.
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. ZD1839 (IRESSA) is an orally active, selective inhibitor of EGFR-TK. This study examined the effects of ZD1839 in TFK-1 and HuCCT1, 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 HuCCT1. The TFK-1 and HuCCT1 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 G1 arrest. Moreover, concurrent evaluation of the expression of p27(Kip1) protein and Jun activating domain-binding protein 1 (Jab1) with ZD1839 by Western blotting analysis was performed. It was found that ZD1839 activity causes an increase of p27(Kip1) stability that correlates with Jab1 down-regulation. Thus, ZD1839 affects key cellular pathways, controlling cell proliferation and apoptosis. Furthermore, the treatment of TFK-1 with ZD1839 reduced the cell survival after radiation exposure. ZD1839 in combination with radiation produced a dose-dependent and synergic inhibitory effect on cellular proliferation. In conclusion, these results suggest that ZD1839 may have clinical activity against cholangiocarcinoma.
Department of of Hepato-Billary-Pancreatic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Shinichi
S
Yabuuchi
Yu
Y
Katayose
Akira
A
Oda
Masamichi
M
Mizuma
Satoru
S
Shirasou
Tsuyoshi
T
Sasaki
Kuniharu
K
Yamamoto
Masaya
M
Oikawa
Toshiki
T
Rikiyama
Tohru
T
Onogawa
Hiroshi
H
Yoshida
Hideo
H
Ohtuska
Fuyuhiko
F
Motoi
Shinichi
S
Egawa
Michiaki
M
Unno
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000528:radiation effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D011799:Quinazolines / Q000627:therapeutic use*; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured; D014965:X-Rays
D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011799:Quinazolines; D050760:Cyclin-Dependent Kinase Inhibitor p27; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib