Gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, up-regulates p27KIP1 and induces G1 arrest in oral squamous cell carcinoma cell lines.
High expression of epidermal growth factor receptor (EGFR) is frequently observed in many solid tumor types including oral squamous cell carcinomas (OSCC). Recently, the results of preclinical studies and early clinical trials targeting the EGFR have shown evidence of the activity. In this study, gefitinib ('Iressa', ZD1839), an EGFR-tyrosine kinase inhibitor, inhibited cell proliferation and upregulated p27KIP1 in OSCC cells. Growth inhibition was observed in OSCC xenografts when mice were treated with gefitinib in vivo. A flow cytometric analysis demonstrated that treatment with gefitinib induced accumulation in G1 phase, accompanied by a decrease in the percentage of cells in S phase. Apoptosis was not seen in this study. Cell growth was inhibited by an increase of the cell cycle inhibitor p27KIP1 and a decrease of its ubiquitin ligase subunit Skp2.
Shintani
Satoru
S
Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, 454 Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. satoru@m.ehime-u.ac.jp
Li
Chunnan
C
Mihara
Mariko
M
Yano
Junya
J
Terakado
Nagaaki
N
Nakashiro
Koh-ichi
K
Hamakawa
Hiroyuki
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D000077156:Gefitinib; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000627:therapeutic use*; D016196:S Phase / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D000077156:Gefitinib