np-031112 and Diabetes-Mellitus

Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and β-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation. In addition, a detailed description of the small molecule inhibitors of GSK-3 with different mode of action discovered or specifically developed for GSK-3 has been presented. Furthermore, some clues for the future optimization of these promising molecules to develop specific drugs inhibiting GSK-3, for the treatment of associated disease conditions have also been discussed.

Topics: Alzheimer Disease; Animals; Bipolar Disorder; Clinical Trials as Topic; Diabetes Mellitus; Drug Discovery; Glycogen Synthase Kinase 3; Humans; Models, Molecular; Neoplasms; Patents as Topic; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction

Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant

Topics: Adenocarcinoma; Adenylate Kinase; Antineoplastic Agents; bcl-X Protein; Berberine; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Diabetes Mellitus; Dietary Supplements; Disease Progression; Doxorubicin; Female; Fluorouracil; Gemcitabine; Glycogen Synthase Kinase 3 beta; Glycolysis; Humans; Inhibitory Concentration 50; Malaria; MCF-7 Cells; Metformin; Molecular Targeted Therapy; Neoplasm Metastasis; Nitrophenols; Pancreatic Neoplasms; Piperazines; Protein Kinase Inhibitors; Signal Transduction; Sulfonamides; Thiadiazoles; Tumor Stem Cell Assay