Document Detail


The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism.
MedLine Citation:
PMID:  17404024     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to characterize the effects of ZD1839 with regard to human OSCC cell growth and invasion/migration. The YD-10B cells represent a highly invasive human OSCC cell line, which has a frame shift p53 mutation. ZD1839 inhibited the growth of the cell line in a time- and dose-dependent manner. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest. This induction of a G1 cell cycle arrest was associated with the upregulation of cyclin-dependent kinase inhibitors (CDKI) p27(KIP1) and p21(CIP1/WAF1). The upregulation of CDKI in ZD1839 treated cell lines may be mediated by a p53-independent and hnRNPC1/C2-dependent pathway. In addition, 100 nM ZD1839 demonstrated that both MMP-2 and MMP-9 enzyme activity were decreased by approximately 25-30%. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that ZD1839 downregulated the uPAR mRNA level. These results might be associated with the reduction of MMP-2 and MMP-9 activities. The current in vitro study indicates that the inhibition of proliferation and invasion/migration in OSCC cell lines by ZD1839 results in an anticancer effect via multiple cellular and molecular mechanisms, and suggests that ZD1839 may be useful in inhibiting and/or preventing metastasis.
Authors:
Eun Ju Lee; Jin Ha Whang; Nam Kyeong Jeon; Jin Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Annals of the New York Academy of Sciences     Volume:  1095     ISSN:  0077-8923     ISO Abbreviation:  Ann. N. Y. Acad. Sci.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-04-03     Completed Date:  2007-05-08     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7506858     Medline TA:  Ann N Y Acad Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  113-28     Citation Subset:  IM    
Affiliation:
Department of Oral Pathology, Oral Cancer Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University, School of Dentistry, 134 Shinchon-Dong, Sudaemun-Ku, Seoul 120-752, Korea.
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Squamous Cell / drug therapy*,  enzymology
Cell Line, Tumor
Cell Proliferation / drug effects*
Humans
Matrix Metalloproteinases / physiology*
Neoplasm Invasiveness
Protein Kinase Inhibitors / pharmacology*
Quinazolines / pharmacology*
Receptor, Epidermal Growth Factor / antagonists & inhibitors
Receptors, Cell Surface / physiology*
Receptors, Urokinase Plasminogen Activator
Tongue Neoplasms / drug therapy*,  enzymology
Tumor Suppressor Protein p53 / physiology*
Chemical
Reg. No./Substance:
0/PLAUR protein, human; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/Receptors, Cell Surface; 0/Receptors, Urokinase Plasminogen Activator; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.24.-/Matrix Metalloproteinases; S65743JHBS/gefitinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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