Document Detail

Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion.
MedLine Citation:
PMID:  18021219     Owner:  NLM     Status:  MEDLINE    
Increased expression of the receptor tyrosine kinase c-Met has been shown to correlate with enhanced cell proliferation, motility, and invasion. The objectives of this study were to characterize total and activated c-Met expression in both normal and malignant human ovarian epithelial cells and to determine the effects of inhibiting the activation of c-Met on ovarian epithelial cell growth, motility, and invasion. Total c-Met was overexpressed in 82 (68%) of 119 ovarian carcinomas, as shown by immunohistochemistry. Quantitative reverse transcription-polymerase chain reaction and Western blot analyses revealed that ovarian carcinoma cell lines had higher levels of c-Met messenger RNA, total protein, and activated protein expression compared to normal ovarian epithelial cell cultures. Using a specific adenosine triphosphate-competitive small-molecule inhibitor, SU11274, activated c-Met was decreased in normal and ovarian carcinoma cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cell growth inhibition directly correlated to the level of activated c-Met detected in each cell line (r =-0.87, P = 0.012). Using modified Boyden chamber assays, ovarian carcinoma cells treated with SU11274 demonstrated significantly decreased cell motility and invasion compared to untreated cells (P = 0.003 and P < 0.001, respectively). These data indicate that c-Met is overexpressed in the majority of malignant ovarian epithelial cells both in vivo and in vitro and that decreasing activated c-Met in vitro can significantly decrease ovarian carcinoma cell growth, motility, and invasion. Developing therapies that specifically inhibit the activation of c-Met may represent a novel therapeutic modality for patients with ovarian carcinomas expressing high levels of c-Met.
E C Koon; P C Ma; R Salgia; W R Welch; J G Christensen; R S Berkowitz; S C Mok
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-11-16
Journal Detail:
Title:  International journal of gynecological cancer : official journal of the International Gynecological Cancer Society     Volume:  18     ISSN:  1525-1438     ISO Abbreviation:  Int. J. Gynecol. Cancer     Publication Date:    2008 Sep-Oct
Date Detail:
Created Date:  2008-10-01     Completed Date:  2009-01-07     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9111626     Medline TA:  Int J Gynecol Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  976-84     Citation Subset:  IM    
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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MeSH Terms
Adenosine Triphosphate / metabolism*
Cell Line
Cell Proliferation / drug effects
Gene Expression Regulation, Neoplastic
Indoles / pharmacology*
Ovarian Neoplasms / enzymology*,  genetics,  pathology*
Piperazines / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*,  metabolism
Sulfonamides / pharmacology*
Grant Support
Reg. No./Substance:
0/((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); 0/Indoles; 0/Piperazines; 0/Sulfonamides; 56-65-5/Adenosine Triphosphate; EC Proteins c-met

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