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Small molecule c‐MET inhibitor PHA665752: Effect on cell growth and motility in papillary thyroid carcinoma
Author(s) -
Chattopadhyay Chandrani,
ElNaggar Adel K.,
Williams Michelle D.,
Clayman Gary L.
Publication year - 2008
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.20816
Subject(s) - c met , hepatocyte growth factor , apoptosis , cell growth , cancer research , cell culture , thyroid carcinoma , motility , papillary thyroid cancer , downregulation and upregulation , cell , chemistry , biology , microbiology and biotechnology , thyroid , endocrinology , receptor , biochemistry , gene , genetics
Background c‐Met is upregulated in papillary thyroid carcinoma (PTC) and can be an attractive therapeutic target. We tested the effects of the small molecule c‐met inhibitor PHA665752 in blocking c‐met–dependent phenotypic effects in PTC cell lines. Methods PTC patient tissues and cell lines were evaluated for c‐met expression. The effect of PHA665752 on c‐met phosphorylation, downstream signaling, hepatocyte growth factor (HGF)–dependent cell growth, and induction of apoptosis was studied. The IC 50 of PHA665752 in c‐met–expressing PTC cells was determined, and growth curves at 0.1×, 1×, and 10× IC 50 concentrations were obtained. Poly(ADP‐ribose) polymerase (PARP) and caspase‐9‐processing post‐PHA665752 treatment were studied as markers of apoptosis, and assays analyzing HGF‐dependent cell invasion and migration in the presence and absence of PHA665752 were done. Results c‐Met was upregulated in most of the patient tissues with PTC and in many PTC cell lines. PHA665752 specifically inhibited c‐met phosphorylation, c‐met–dependent cell growth, signal transduction, cell survival, cell invasion, and migration in PTC cells with high c‐met. Conclusions PHA665752 is an effective and specific inhibitor of c‐met in PTC cells with high levels of c‐met expression. © 2008 Wiley Periodicals, Inc. Head Neck, 2008