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.


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.


CONCLUSIONS
The antiproliferative effects of gefitinib may be, at least in part, due to the inhibition of E2F-1 expression and telomerase activity.
Suenaga
Mitsuhiro
M
Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan. suenagam@m3.kufm.kagoshima-u.ac.jp
Yamaguchi
Akihiko
A
Soda
Hiroshi
H
Orihara
Koji
K
Tokito
Yuichi
Y
Sakaki
Yoshimune
Y
Umehara
Megumi
M
Terashi
Kenji
K
Kawamata
Nakaaki
N
Oka
Mikio
M
Kohno
Shigeru
S
Tei
Chuwa
C
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014846:Vulvar Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011799:Quinazolines; D012333:RNA, Messenger; D066246:ErbB Receptors; C509186:TERT protein, human; D019098:Telomerase; D000077156:Gefitinib