Visit our Expo - Redox and Inflammation signaling 2012

IV. Protein kinase inhibitors: insights into drug design from structure Poster IV, 3
The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 (‘Iressa)
Suppresses Proliferation and Invasion of Human Oral Squamous Carcinoma Cells via
MMP, uPAR Dependent Mechanism
Eun J. Lee, Jin H. Whang, Nam K. Jeon, Young E. Kwak and Jin Kim
Department of Oral Pathology, Oral Cancer Research Institute, BK21 project for
Medical Science, Yonsei University College of Dentistry, Seoul, 120-752, KOREA
E-mail:e16lee@yumc.yonsei.ac.kr
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 (MMP) have
been implicated in the development of squamous-cell carcinoma of oral cancer. This study
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. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in
cell cycle progression and a G1 arrest, which was associated with the up-regulation of cyclindependent
kinase inhibitors (CDKI) p27KIP1 and p21CIP1/WAF1. The up-regulation of
CDKI may be mediated by a p53-independent and hnRNPC1/C2-dependent pathway. In
addition, 100nM ZD1839 demonstrated that both MMP-2 and MMP-9 enzyme activity were
decreased by ~25-30%. 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. (This study was supported by the BK21 project for
Medical Science, and by a grant of the national Cancer control R&D Program (02-PJ1-PG3-
20801-0015) and 2003(No. 0320230), Ministry of Health & Welfare, Republic of Korea.)
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