The effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser in bile duct carcinoma cell lines.
The signaling pathway that is initiated by binding of epidermal growth factor receptor (EGFR) and results in sustained signaling through PI3K plays an important role in a tumor's response to ionizing radiation. The current in vitro study explored both the effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser for bile duct carcinoma cell lines and ZD1839's general effects on cell growth in the same two lines. Secondly, we ensured suppression of radiation-induced phosphorylation of EGFR by ZD1839 using an immunoprecipitation technique. Furthermore, we examined radiation-induced phosphorylation of ERK, p38, JNK, and AKT with or without inhibitor with use of Western blot techniques and performed clonogenic assays to confirm radiosensitivity in the presence of a drug. ZD1839 inhibited cell growth of both cell lines and suppressed radiation-induced phosphorylation of EGFR. After exposure to radiation, there was an increase in phosphorylation of AKT as shown by Western blot. Treatment with either ZD1839 or LY294002 (the latter, a PI3K inhibitor) suppressed phosphorylation of AKT by Western blot. Both ZD1839 and LY294002 significantly suppressed colony formation by clonogenic assay; however, U0126 (a MEK1/2 inhibitor), SB203580 (a p38 inhibitor), and SP600125 (a JNK inhibitor) had no effect on colony formation. These results suggest that AKT may be a useful target molecule for enhancement of radiotherapy effect and that ZD1839 may have an important role in combination with radiotherapy for patients with bile duct carcinoma.
Miyata
Hideki
H
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biochemical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734-8551, Japan. hideki00@hiroshima-u.ac.jp
Sasaki
Tamito
T
Kuwahara
Kenichi
K
Serikawa
Masahiro
M
Chayama
Kazuaki
K
D000873:Anthracenes / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002867:Chromones / Q000494:pharmacology; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000873:Anthracenes; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C113580:U 0126; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000077156:Gefitinib