title: Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.
authors: Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors: P
authors: P
authors: Dao
authors: Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors: N
authors: N
authors: Smith
authors: Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 25 rue de Dr Roux, 75724 Paris, France.
authors: D
authors: D
authors: Scott-Algara
authors: Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors: C
authors: C
authors: Garbay
authors: Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors: J P
authors: JP
authors: Herbeuval
authors: Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France. Electronic address: huixiong.chen@parisdescartes.fr.
authors: H
authors: H
authors: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014227:Triazines; C000597758:methyl 2-(4-(3,4,5-trimethoxyphenylamino)imidazo(1,2-a)(1,3,5)triazin-2-ylamino)benzoate; D058539:Phosphatidylinositol 3-Kinase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: FAK inhibitor; PI3K/AKT pathway; Pancreatic cancer cell lines; TRAIL; c-FLIP