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...

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Bibliographic Details
Published in:Cancer letters 2015-04, Vol.360 (1), p.48-59
Main Authors: Dao, P, Smith, N, Scott-Algara, D, Garbay, C, Herbeuval, J.P, Chen, H
Format: Article
Language:English
Subjects:
Adapter proteins
Antineoplastic Agents
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
c-FLIP
Cancer therapies
CASP8 and FADD-Like Apoptosis Regulating Protein
CASP8 and FADD-Like Apoptosis Regulating Protein - genetics
CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism
Caspases
Caspases - metabolism
Cell Line, Tumor
Chemotherapy
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Resistance, Neoplasm - drug effects
Enzyme Activation
FAK inhibitor
Focal Adhesion Kinase 1
Focal Adhesion Kinase 1 - antagonists & inhibitors
Focal Adhesion Kinase 1 - genetics
Focal Adhesion Kinase 1 - metabolism
Hematology, Oncology and Palliative Medicine
Humans
Imidazoles
Imidazoles - pharmacology
Immunology
Immunotherapy
Innate immunity
Kinases
Life Sciences
Ligands
Medical prognosis
Molecular Targeted Therapy
Mortality
Pancreatic cancer
Pancreatic cancer cell lines
Pancreatic Neoplasms
Pancreatic Neoplasms - enzymology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinase - metabolism
PI3K/AKT pathway
Protein Kinase Inhibitors
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-akt - metabolism
RNA Interference
Signal Transduction
Signal Transduction - drug effects
Studies
Time Factors
TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand - pharmacology
TRAIL
Transfection
Triazines
Triazines - pharmacology
Tumors
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Summary: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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2015.02.016