title: Small molecule inhibitor of c-Met (PHA665752) suppresses the growth of ovarian cancer cells and reverses cisplatin resistance.
abstract: c-Met as a tyrosine-kinase receptor plays a major role in tumorigenesis, invasion, and metastatic spread of human tumors, including ovarian cancer. Expressing high levels of c-Met proteins is often associated with resistance to chemotherapy and an adverse prognosis. In this study, we have determined the effect of PHA665752, a small molecule inhibitor of c-Met proteins, with and without cisplatin and the role of c-Met in several ovarian cancer cell lines having high c-Met expression. The methyl thiazolyl tetrazolium (MTT) assay was used to detect cell proliferation, and apoptosis was evaluated by flow cytometry. Western blotting was carried out to determine protein expression levels. Gene silencing was used to detect the influence of c-Met gene silence on the resistance to cisplatin. Compared to more sensitive ovarian cancer cell lines SKOV3 and 3AO, we found that the expression of c-Met was significantly increased in SKOV3(DDP), OVCAR3, and OV-90 ovarian cancer cell lines, which were resistant to cisplatin. Our data indicated that cisplatin sustained activated phosphor-Met in SKOV3(DDP), OVCAR3, and OV-90 cell lines. We also observed a significant transient activation of c-Met phosphorylation in SKOV3 and 3AO cells. Treatment with PHA665752 inhibited c-Met expression inhibited cell growth, induced apoptosis, and enhanced cisplatin-induced proliferation inhibition and apoptosis in c-Met over-expressed cell lines. In addition, blocking c-Met expression with small interfering RNA (siRNA) overcame the resistance of cancer cells to cisplatin. Thus, blocking c-Met expression presents a promising therapeutic approach for ovarian cancer.
authors.affiliation: Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Enze
authors.initials: E
authors.lastname: Li
authors.affiliation: Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Stomatology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150000, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Condensed Matter Science and Technology Institute, Harbin Institute of Technology, Harbin, 150080, China. zhangzhiguo@hit.edu.cn.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China. dzk@psu.edu.|Department of Mathematics and Materials Research Institute, Pennsylvania State University, 164 Materials Research Lab, University Park, PA, 16802, USA. dzk@psu.edu.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; D007211:Indoles; D034741:RNA, Small Interfering; D013450:Sulfones; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; Ovarian cancer; PHA665752; c-Met