Study of critical role of c-Met and its inhibitor SU11274 in colorectal carcinoma.

Abstract

c-Met plays an important role in colorectal tumorigenesis and disease progression and thus is believed to be an attractive inhibitory target for receptor molecular therapeutic. SU11274 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Our study had investigated the relationship between the high expression of c-Met and colorectal carcinoma and the effect of c-Met inhibitor SU11274 in colorectal carcinoma in vitro and vivo. Immunohistochemistry was used to detect the expression of c-Met in 60 patients with colorectal cancer and 20 patients with benign adenoma and surrounding normal colon tissues. The effect of SU11274 on human colorectal carcinoma LoVo cells was detected by Western blot and MTT. And the influence of SU11274 on cell cycle was determined by flow cytometry. In addition, LoVo cell-transplanted tumor growth and expression of c-Met in nude mice was examined for inhibition of SU11274 in vivo. We found c-Met had high expression and was closely related to lymph node metastasis and TNM stage in colorectal carcinoma tissues. SU11274 significantly suppressed the phosphorylation of c-Met as well as the survival and proliferation of LoVo cell lines. G1-phase arrest was also induced by SU11274. SU11274 apparently restrained the growth of the xenograft tumor in nude mice. Our data suggest developing therapies that specifically inhibit the activation of c-Met may represent a novel therapeutic modality for patients with colorectal carcinoma expressing high levels of c-Met.

• Authors: Wei Gao, Xue Bing, MingYan Li, Zhanhua Yang, Ying Li, Hua Chen
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 30 Issue 2 Pg. 546 (Jun 2013) ISSN: 1559-131X [Electronic] United States
• PMID: 23536000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ((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)
• Indoles
• Piperazines
• Protein Kinase Inhibitors
• Sulfonamides
• RON protein
• Receptor Protein-Tyrosine Kinases

Topics

• Adenoma (drug therapy, enzymology, pathology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, enzymology, secondary)
• Female
• Humans
• Indoles (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Piperazines (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, physiology)
• Sulfonamides (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays (methods)