PF-2341066 combined with celecoxib promotes apoptosis and inhibits proliferation in human cholangiocarcinoma QBC939 cells.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with high incidence and an average age of onset of 50-70 years old. However, at present there is no effective treatment for this disease. The aim of the present study was to investigate the effects of a c-Met inhibitor, PF-2341066 and a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on c-Met and COX-2 expression, proliferation and apoptosis. The results demonstrated that c-Met and COX-2 are highly expressed in hepatobiliary calculus with cholangiocarcinoma. PF-2341066 was able to downregulate the expression of c-Met and COX-2 in a dose-dependent manner at the mRNA and protein levels in human cholangiocarcinoma QBC939 cells. Furthermore, combined treatment with PF-2341066 with celecoxib downregulated the mRNA expression of both genes, inhibited cell proliferation and promoted cell apoptosis. It was also demonstrated that PF-2341066 and celecoxib treatment was able to restrict the expression of vascular endothelial growth factor (VEGF). The results of the present study suggest that PF-2341066 and celecoxib may inhibit the development of cholangiocarcinoma by downregulating the expression of c-Met and COX-2 to inhibit cell proliferation, promote apoptosis and prevent VEGF-mediated tumor angiogenesis. Co-treatment with PF-2341066 and celecoxib may be a potential therapeutic strategy for hepatobiliary calculus with cholangiocarcinoma.

[1]  G. Gores,et al.  Pathogenesis, diagnosis, and management of cholangiocarcinoma. , 2013, Gastroenterology.

[2]  Jin‐Young Jang,et al.  Is c-Met oncoprotein expression an adverse prognosticator in extrahepatic bile duct cancer treated with curative resection followed by adjuvant chemoradiotherapy? , 2016, Clinical and Translational Oncology.

[3]  A. Ristimäki,et al.  Expression of cyclooxygenase-2 in human gastric carcinoma. , 1997, Cancer research.

[4]  Y. Yatabe,et al.  Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. , 1998, Cancer research.

[5]  J. Masferrer,et al.  Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. , 2002, Cancer research.

[6]  K. Schrör,et al.  Cyclooxygenase-2 expression in human esophageal carcinoma. , 1999, Cancer research.

[7]  Yasunori Sato,et al.  Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies, immunophenotypes, and development-related molecules. , 2013, Human pathology.

[8]  S. Akinaga,et al.  A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer , 2014, Investigational New Drugs.

[9]  S. Zou,et al.  Celecoxib inhibits proliferation and induces apoptosis via prostaglandin E2 pathway in human cholangiocarcinoma cell lines. , 2003, World journal of gastroenterology.

[10]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[11]  D. Jeong,et al.  Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis , 2015, Annals of surgical treatment and research.

[12]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[13]  A. Bauer,et al.  YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors , 2015, Hepatology.

[14]  J. Masferrer,et al.  COX‐2 is expressed in human pulmonary, colonic, and mammary tumors , 2000, Cancer.

[15]  V. Paradis,et al.  EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition. , 2014, Journal of hepatology.

[16]  L. Shun.  An Orally Available Small-Molecule Inhibitor of c-Met,PF-2341066,Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic Mechanisms , 2010 .

[17]  R. DuBois,et al.  Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Tseng,et al.  Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines , 2015, Cancer Gene Therapy.

[19]  T. Patel,et al.  Tumour cell–derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth , 2015, Journal of extracellular vesicles.

[20]  Y. Hosomi,et al.  Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. , 2000, Lung cancer.

[21]  S. Dubinett,et al.  COX-2 inhibition and lung cancer. , 2004, Seminars in oncology.

[22]  S. Pothula,et al.  The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: antiangiogenic implications in pancreatic cancer. , 2014, Carcinogenesis.

[23]  A. Sckell,et al.  The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice , 2006, BMC Cancer.

[24]  W. Jiang,et al.  Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. , 2005, Critical reviews in oncology/hematology.

[25]  Zhigang Hu,et al.  Clinical Profile of Cyclooxygenase-2 Inhibitors in Treating Non-Small Cell Lung Cancer: A Meta-Analysis of Nine Randomized Clinical Trials , 2016, PloS one.

[26]  D. Ribatti,et al.  A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target , 2014, Clinical Cancer Research.

[27]  L. Ellis,et al.  Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  J. Isola,et al.  Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. , 2002, Cancer research.

[29]  A. Frankel,et al.  c-Met targeted therapy of cholangiocarcinoma. , 2008, World journal of gastroenterology.

[30]  S. De Flora,et al.  Modulation by licofelone and celecoxib of experimentally induced cancer and preneoplastic lesions in mice exposed to cigarette smoke. , 2015, Current cancer drug targets.

[31]  K. Seibert,et al.  Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. , 2000, Oncology reports.

[32]  J. Isner,et al.  Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. , 1997, The American journal of pathology.