Subject(s)
Cytoskeletal Proteins/metabolism , DNA-Binding Proteins/pharmacology , Oncogene Proteins/pharmacology , Trans-Activators/metabolism , Trans-Activators/pharmacology , Tumor Suppressor Proteins/pharmacology , Zebrafish Proteins/pharmacology , Animals , Apoptosis/drug effects , Cell Line , Cell Proliferation/drug effects , Cytoskeletal Proteins/antagonists & inhibitors , Gene Expression/drug effects , Genes, Reporter/genetics , Maf Transcription Factors, Large , Mice , Mutation/genetics , Trans-Activators/antagonists & inhibitors , beta CateninSubject(s)
Drug Screening Assays, Antitumor/methods , Genes, ras/drug effects , Signal Transduction/drug effects , Sulindac/analogs & derivatives , Zebrafish Proteins , Animals , Annexin A5/analysis , Annexin A5/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Apoptosis/physiology , Cell Division/drug effects , Cell Division/physiology , Cell Line , Cell Line, Transformed , Cell Survival/drug effects , Cell Survival/physiology , Cell Transformation, Neoplastic/genetics , Combinatorial Chemistry Techniques , Dose-Response Relationship, Drug , Epithelial Cells/drug effects , Genes, ras/genetics , Genes, ras/physiology , Inhibitory Concentration 50 , Microscopy, Fluorescence , Phenotype , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/physiology , Signal Transduction/physiology , Structure-Activity Relationship , Sulindac/chemistry , Sulindac/pharmacology , Wnt ProteinsSubject(s)
Proto-Oncogene Proteins c-raf/metabolism , Signal Transduction/drug effects , Sulindac/analogs & derivatives , ras Proteins/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blotting, Western , Cell Line, Transformed/drug effects , Cell Transformation, Neoplastic/genetics , Dose-Response Relationship, Drug , Genes, ras/genetics , Guanosine Triphosphate/metabolism , Inhibitory Concentration 50 , Kinetics , Magnetic Resonance Spectroscopy , Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Phosphorylation/drug effects , Protein Binding/drug effects , Signal Transduction/physiology , Spectrometry, Fluorescence , Sulindac/metabolism , Sulindac/pharmacology , ras Proteins/geneticsABSTRACT
The nonsteroidal anti-inflammatory drug Sulindac has chemopreventive and antitumorigenic properties. Its metabolites induce apoptosis and inhibit signaling pathways critical for malignant transformation, including the Ras pathway. Here we show that the new Sulindac derivative IND 12 reverses the phenotype of Ras-transformed MDCK-f3 cells and restores an untransformed epithelioid morphology characterized by growth in monolayers with regular cell-cell adhesions. Moreover, IND 12 treatment induces the expression at membranes of the cell adhesion protein E-cadherin and increases the level of the E-cadherin-bound beta-catenin. As a consequence, IND 12-treated MDCK-f3 cells lose their invasion capacity and regain the ability to aggregate. In the presence of IND 12, MDCK-f3 cells show regenerated expression and activity ratios of the small GTPases Rac and Rho normally found in untransformed MDCK cells. Strikingly, IND 12 treatment decreases the levels of phosphorylated mitogen-activated protein kinases, which are downstream substrates of the Ras-regulated Raf/mitogen-activated protein kinase pathway, and the level of Ras-induced activation of gene expression. Our findings identify a novel drug with high potential in cancer therapy by targeting Ras-induced cell transformation.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Transformation, Neoplastic , Genes, ras/drug effects , Sulindac/pharmacology , Trans-Activators , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cadherins/metabolism , Cell Aggregation/drug effects , Cell Line, Transformed , Cytoskeletal Proteins/metabolism , Dogs , Enzyme Inhibitors/pharmacology , Epithelial Cells/cytology , Epithelial Cells/drug effects , Genes, ras/physiology , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Sulindac/analogs & derivatives , beta CateninABSTRACT
Metabolites of the non-steroidal anti-inflammatory drug Sulindac inhibit cell proliferation by affecting several intracellular signaling pathways including the tumorigenic Ras/Raf/MAPK pathway. Here, we report the synthesis of eight new indene derivatives derived from the Sulindac structure, and present data on their anti-proliferative properties and their effects on the p21ras protein.
