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1.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
2.
Turk Neurosurg ; 29(4): 513-521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984989

RESUMO

AIM: To investigate the apoptotic and molecular effects of glycogen synthase kinase-3 (GSK-3) in glioblastoma multiforme (GBM). MATERIAL AND METHODS: Human primary glioblastoma cell line (U-87 MG) and the human fetal glial cell line (SVGp12) were used. The cells were exposed to the different doses of GSK inhibitor for 24, 48 and 72 hours. Induction of apoptosis was assessed by DNA fragmentation (TUNEL) assay. EGFR and NF-kB expression was evaluated by immunofluorescence analyses. RESULTS: GSK-3 inhibitor IX induced cytotoxicity and apoptosis in dose-dependent manner in GBM cells. Our results indicated that GSK-3 inhibitor IX induces apoptosis, resulting in a significant decrease in the expression of NF-kB and EGF. CONCLUSION: Inhibition through GSK-3 has been found promising in creating therapeutic management of GBM cells. Proliferation, differentiation, cell cycle regulation, and apoptosis are mechanisms that must be interpreted as a whole. Components associated with EGFR, NF-kB, and apoptosis affect the mechanism solely and collectively. Our collective data suggest that GSK-3 inhibitor IX inhibited cellular proliferation and induced apoptotic events by modulating EGFR and NF-kB expression in GBM cells. GSK-3 inhibition holds promise for the development of new approaches for the therapeutic management of GBM cells.


Assuntos
Apoptose/fisiologia , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Inibidores Enzimáticos/farmacologia , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
3.
Malar J ; 18(1): 89, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898128

RESUMO

BACKGROUND: Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. METHODS: 4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. RESULTS: The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was shown that the (+)-enantiomer acts as eutomer. CONCLUSIONS: The attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines. These molecules show axial chirality, a feature of high impact for biological activity. The findings can be exploited for the development of improved selective PfGSK-3 inhibitors.


Assuntos
Antimaláricos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Piridinas/farmacologia , Células HEK293 , Humanos , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 171: 221-234, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30925338

RESUMO

Glycogen synthase kinase 3α (GSK-3α) plays a constitutive role in various physiological processes and has been proved to be a therapeutic target for acute myeloid leukemia (AML). In this paper, by means of computer-aided drug design, we discovered a novel chemical series of GSK-3α inhibitors with an IC50 value of 0.033-2.804 µM. The preliminary structure-activity relationship was concluded and, notably, the most potent and isoform-selective compound G28_14 was identified with IC50 values of 33 nM and 218 nM against GSK-3α and -3ß, respectively, exhibiting a nearly ten-fold isoform-selectivity. Further cell viability assays and colony formation assays revealed that G28_14 suppressed cell survival by impairing cell proliferation by up to 90% in two AML cell lines. Moreover, surface marker expression analysis demonstrated that G28_14 induced terminal differentiation with a high level of CD11b, CD11c, and CD14. Western immunoblotting showed that G28_14 isoform-selectively inhibited the phosphorylation of GSK-3α in-cell without activating Wnt/ß-catenin signaling. In addition, to elucidate its structure-activity relationship, the binding mode of this chemical series was proposed using molecular docking and molecular dynamics simulations. Taken together, this chemical series is worth developing as differentiation therapies for the treatment of AML.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
5.
PLoS One ; 14(2): e0211239, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30721232

RESUMO

Serotonin-1B receptors (5-HT1BRs) modulate perseverative behaviors and prepulse inhibition (PPI) in humans and mice. These inhibitory G-protein-coupled receptors signal through a canonical G-protein-coupled pathway that is modulated by GSK-3ß, and a noncanonical pathway mediated by the adaptor protein ß-arrestin2 (Arrb2). Given the development of biased ligands that differentially affect canonical versus noncanonical signaling, we examined which signaling pathway mediates 5-HT1BR agonist-induced locomotor perseveration and PPI deficits, behavioral phenotypes observed in both obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD). To assess the role of canonical 5-HT1BR signaling, mice received acute pretreatment with a GSK-3 inhibitor (SB216763 or AR-A014418) and acute treatment with the 5-HT1A/1B receptor agonist RU24969 prior to assessing perseverative locomotor behavior in the open field, and PPI. To determine the role of noncanonical 5-HT1BR signaling, Arrb2 wild-type (WT), heterozygous (HT), and knockout (KO) mice received acute RU24969 treatment prior to behavioral testing. GSK-3 inhibition increased locomotor perseveration overall, and also failed to influence the RU24969-induced perseverative locomotor pattern in the open field. Yet, GSK-3 inhibition modestly reduced RU24969-induced PPI deficits. On the other hand, Arrb2 HT and KO mice showed reduced locomotion and no changes in perseveration overall, in addition to modest reductions in RU24969-induced locomotion and PPI deficits. In conclusion, our data do not support use of either GSK-3 inhibitors or ß-arrestin2 inhibition in treatment of perseverative behaviors.


Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Locomoção , Inibição Pré-Pulso , Receptor 5-HT1B de Serotonina/metabolismo , Transdução de Sinais , beta-Arrestina 2/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Genótipo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indóis/farmacologia , Locomoção/efeitos dos fármacos , Maleimidas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Inibição Pré-Pulso/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , beta-Arrestina 2/genética
6.
Eur J Med Chem ; 168: 58-77, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30798053

RESUMO

Both cholinesterases (AChE and BChE) and kinases, such as GSK-3α/ß, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3α/ß (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3α/ß. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.


Assuntos
Acetilcolinesterase/metabolismo , Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 209: 150-164, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30388586

RESUMO

Glioblastoma multiforme (GBM) is the most malignant and aggressive primary human brain tumors. The regulatory pathways of apoptosis are altered in GBMs, leading to a survival advantage of the tumor cells. Thus, identification of target molecules, which are effective in triggering of the cell death mechanisms in GBM, is an essential strategy for therapeutic purposes. Glycogen synthase kinase-3 (GSK-3) plays an important role in apoptosis, proliferation and cell cycle. This study focused on the effect of GSK-3 inhibitor IX in the GBM cells. Apoptosis induction was determined by Annexin-V assay, multicaspase activity and immunofluorescence analyses. Concentration-dependent effects of GSK-3 inhibitor IX on the cell cycle were also evaluated. Moreover, the effect of GSK inhibitor on the cellular biomolecules was assessed by using ATR-FTIR spectroscopy. Our assay results indicated that GSK-3 inhibitor IX induces apoptosis, resulting in a significant increase in the expression of caspase-3 and caspase-8 proteins. Cell cycle analyses revealed that GSK-3 inhibitor IX leads to dose-dependent G2/M-phase cell cycle arrest. Based on the FTIR data, treatment of GBM cells causes dysregulation in the carbohydrate metabolism and induces apoptotic cell death which was characterized by the spectral alterations in nucleic acids, an increment in the lipid amount with disordering state and compositional changes in the cellular proteins. These findings suggest that GSK-3 inhibitor IX exhibits anti-cancer effects by inducing apoptosis and changing biomolecular structure of membrane lipids, carbohydrates, nucleic acids and proteins, and thus, may be further evaluated as a potential effective candidate agent for the GBM combination therapies.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glioblastoma/patologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Proliferação de Células , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Humanos , Células Tumorais Cultivadas
8.
PLoS One ; 13(12): e0208094, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30557366

RESUMO

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been reported in some cancer cells, including AGS human gastric adenocarcinoma cells. Reducing this resistance might shed light on the treatment of human gastric adenocarcinoma. In this study, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors can restore TRAIL responsiveness in gastric adenocarcinoma cells. The effect of two GSK-3 inhibitors, SB-415286, and LiCl, on apoptosis signaling of TRAIL in human gastric adenocarcinoma cell lines and primary gastric epithelial cells was analyzed. Both inhibitors can sensitize gastric adenocarcinoma cells, but not primary gastric epithelial cells, to TRAIL-induced apoptosis by increasing caspase-8 activity and its downstream signal transmission. Adding p53 siRNA can downregulate GSK-3 inhibitor-related sensitization to TRAIL-induced apoptosis and caspase-3 activity. GSK-3 inhibitors strongly activate the phosphorylation of JNK. Inhibition of JNK leads to earlier and more intense apoptosis, showing that the activation of JNK may provide anti-apoptotic equilibrium of pro-apoptotic cells. Our observations indicate that GSK-3 inhibitors can sentize AGS gastric adenocarcinoma cells to TRAIL-induced apoptosis. Therefore, in certain types of gastric adenocarcinoma, GSK-3 inhibitor might enhance the antitumor activity of TRAIL and mightbe a promising candidate for the treatment of certain types of gastric adenocarcinoma.


Assuntos
Adenocarcinoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Aminofenóis/farmacologia , Aminofenóis/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Cloreto de Lítio/farmacologia , Cloreto de Lítio/uso terapêutico , Maleimidas/farmacologia , Maleimidas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/patologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
9.
Oncol Rep ; 40(4): 2005-2013, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066938

RESUMO

Cancer stem cells (CSCs) are considered to be tumor­initiating cells, responsible for tumor invasive growth and dissemination to distant organ sites. Typically, radiation treatment and chemotherapy should target CSCs. However, current research investigating CSCs is impeded by the difficulty of isolating pure CSCs and maintaining them in vitro. In the present study, the synergistic inhibition of glycogen synthase kinase 3 and mitogen­activated protein kinase kinase using small molecules, CHIR99021 and PD184352, efficiently generated CSCs from immortalized human mammary epithelial cells (HMLEs) and resulted in the acquisition of mesenchymal traits and the expression of epithelial­mesenchymal transition markers. The cell proliferation, invasion and migration of HMLE cells were significantly promoted by CHIR99021 and PD184352 (P<0.05). Furthermore, the cell cycle was shifted from the G0/G1 phase to the G2/M phase, and the apoptotic rate was suppressed in HMLE cells following treatment with CHIR99021 and PD184352. Compared with control group, the stimulated cells exhibited an increased ability to form mammospheres and regenerate a tumor. In addition to these properties, the induced cells also exhibited notable chemotherapy resistance. In vivo, the treatment of cells with CHIR99021 and PD184352 promoted the growth of HMLE­engrafted tumor types. These results provide a practical strategy for the generation of CSCs using small molecules in vitro, which provides a cell resource that may be used for drug screening. Additionally, the present results additionally highlighted the synergistic functions of Wnt and mitogen­activated protein kinase kinase signaling pathways in tumorigenesis.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , MAP Quinase Quinase 1/antagonistas & inibidores , Células-Tronco Neoplásicas/patologia , Proteínas Wnt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Biomarcadores Tumorais/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos SCID , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Drug Res (Stuttg) ; 68(8): 436-443, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29388174

RESUMO

GSK-3 inhibitors are an emerging tool for clinical interventions in human diseases and represent a niche area in combinational therapy. They possess diverse facets in applications of nervous system disorders, Type 2 diabetes, regenerative medicine and cancer. However, conflicting reports suggest the controversial role of GSK-3 inhibitors in cancers. This review aims to highlight the rise of GSK-3 inhibitors as tools for molecular-targeted research and its shift to a promising drug candidate. The review also focuses on key GSK-3 inhibitors and their roles in cancer and regenerative medicine with special emphasis to tideglusib. In addition, the decisive roles of GSK-3 in various molecular pathways will be concisely reviewed. Finally, this review concludes the emergence of GSK-3 inhibitors as a 'double-edged sword' in the treatment against human diseases cautioning researchers about the potential ramifications of off-target pharmacological effects.


Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Animais , Humanos , Neoplasias/metabolismo , Medicina Regenerativa/métodos
11.
J Pharm Biomed Anal ; 153: 145-151, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29482106

RESUMO

GS87 is a novel, highly specific GSK3 inhibitor, which has shown to induce extensive differentiation of acute myeloid leukemia (AML) cells in early mouse studies and has great potential for therapeutic advancement. This work described the development and validation of an LC-MS/MS method for quantitative determination of GS87 in mouse plasma. In this method, GS87 and T6447952 (a structural analog used as internal standard) were extracted from plasma using hexane as extraction solvent, and separated isocratically on a Waters XTerra® MS C8 column (2.1 × 50 mm, 3.5 µm) using a mobile phase consisting of acetonitrile and 5.00 mM ammonium formate (35:65, v/v) pumped at a flow rate of 0.200 mL min-1. Quantitation of GS87 was done by positive electrospray ionization tandem mass spectrometry operated in multiple-reaction-monitoring (MRM) mode. The method has been validated in accordance with the US Food and drug administration guidelines for bioanalytical method validation. It has linear calibration range of 2.50-250 ng mL-1 with correlation coefficient of >0.999. The intra- and inter- assay accuracy and precision were ≤ ±5 and ≤6%, respectively. The IS normalized recovery of GS87 was 103-106%. The stability studies showed that GS87 was stable under all tested conditions. The method developed has been successfully applied to the measurement of GS87 concentrations in mouse plasma samples from an animal study, and may be useful for further preclinical investigation of GS87.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Plasma/química , Espectrometria de Massas em Tandem/métodos , Acetonitrilos/química , Animais , Calibragem , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos NOD , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
12.
Eur J Med Chem ; 144: 843-858, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29306837

RESUMO

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase which is ubiquitously expressed and is regarded as a regulator for various cellular events and signalling pathways. It exists in two isoforms, GSK-3α and GSK-3ß and can phosphorylate a wide range of substrates. Aberrancy in the GSK-3 activity can lead to various diseases like Alzheimer's, diabetes, cancer, neurodegeneration etc., rendering it an attractive target to develop potent and specific inhibitors. The present review focuses on the recent developments in the area of GSK-3 inhibitors and also enlightens its therapeutic applicability in various disease conditions.


Assuntos
Antineoplásicos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Neoplasias/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Antineoplásicos/química , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Hipoglicemiantes/química , Neoplasias/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Inibidores de Proteínas Quinases/química
13.
Expert Opin Drug Metab Toxicol ; 14(1): 83-90, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29233065

RESUMO

INTRODUCTION: Levodopa (L-DOPA) is the most commonly used drug for Parkinson's disease (PD), but its long-term use is associated with various complications, including L-DOPA-induced dyskinesia (LID). Many studies have suggested that L-DOPA neurotoxicity and LID are associated with glycogen synthase kinase-3 (GSK-3) activation. Areas covered: LID is caused by striatal dopamine (DA) denervation in PD and pulsatile L-DOPA treatment. These factors lead to dysregulated DA transmission, abnormal intracellular signaling and transcription factors in striatal neurons, and altered gene expression and plasticity at corticostriatal synapses. The mechanisms of L-DOPA toxicity involve oxidative stress, L-DOPA oxidation to quinone, mitochondrial dysfunction, and α-synuclein. GSK-3 has been suggested to play key roles in all the mechanisms associated of L-DOPA toxicity and LID in PD. Expert opinion: GSK-3 plays critical roles in L-DOPA-induced neurotoxicity, and the development of specific methods to inhibit GSK-3 function may help prevent L-DOPA neurotoxicity and LID in PD. However, balanced GSK-3 inhibition and less ß-catenin degradation is essential for preventing LID, because too much GSK-3 inhibition increases ß-catenin levels, which is related to cancers.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Quinase 3 da Glicogênio Sintase/metabolismo , Levodopa/efeitos adversos , Animais , Antiparkinsonianos/administração & dosagem , Dopamina/metabolismo , Discinesia Induzida por Medicamentos/enzimologia , Discinesia Induzida por Medicamentos/prevenção & controle , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Levodopa/administração & dosagem , Síndromes Neurotóxicas/enzimologia , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , beta Catenina/metabolismo
14.
Clin Exp Dermatol ; 43(2): 149-157, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29168273

RESUMO

α-Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single-agent therapy for malignant melanoma (MM), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase (GSK)-3 inhibitor CHIR99021, and rapamycin, in combination with a dietary xanthone, α-mangostin, by screening from a kinase inhibitor library for melanogenesis in SK-MEL-2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis-related proteins. We also explored the molecular mechanisms for the apoptosis-inducing effects reported. We found a marked synergistic effect of CHIR99021 or rapamycin in combination with α-mangostin, which we verified through apoptosis-related methods. These data provide a strong rationale for the use of α-mangostin as an adjunct to GSK-3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α-mangostin might be inhibition of phosphatidylinositol 3-kinase/AKT signalling and autophagy, and induction of reactive oxygen species generation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citotoxinas/farmacologia , Melanoma/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Sirolimo/farmacologia , Neoplasias Cutâneas/fisiopatologia , Xantonas/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Citotoxinas/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Sirolimo/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Xantonas/uso terapêutico
15.
Med Chem ; 14(1): 67-73, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28969571

RESUMO

BACKGROUND: Osteoporosis (OP) is a common bone disease, most often diagnosed in post-menopausal women. The majority of OP treatments are focused on manipulation of the patient's hormone levels, therefore, they are associated with significant adverse effects. OBJECTIVE: The study aimed to design, synthesize and evaluate the ß-catenin translocation capability and the alkaline phosphatase (ALP) activation activity of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives. METHOD: The styrene derivatives were synthesized as raw materials, followed by oxidation and condensation reactions, in which 6-aryl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one derivatives (1) were obtained. The 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones (2) were obtained by a condensation reaction of compound 1 with substituted phenacyl chlorides in acetic acid. The target compounds 3,6-diaryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-ones (3a-3c) were prepared by compound 2 with substituted alkyl chloride by Williamson reaction. As to 6-benzyl-3-aryl-7H-thiazolo[3,2- b]-1,2,4-triazin-7-one derivatives as the target compounds, the benzaldehyde and acetylglycine used as raw materials, followed by Erlenmeyer-Plochl reaction, condensation reaction, hydrolysis reaction, condensation reaction, 6-benzyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one derivatives were obtained, and were converted to the target compounds 6-benzyl-3-(hydroxylaryl)-7Hthiazolo[ 3,2-b]-1,2,4-triazin-7-one derivatives (5a-5d) using reaction with substituted α-phenacyl chlorides. Finally, Williamson reaction were used to yield 6-benzyl-3-aryl-7H-thiazolo[3,2-b]- 1,2,4-triazin-7-ones as target compounds (6a-6e). The ß-catenin translocation capability and the ALP activation activity were tested, and the glycogen synthase kinase-3 (GSK-3) inhibition was simulated by molecular docking. RESULTS: Fourteen 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were synthesized and characterized by mass spectra, proton NMR and infrared spectra, the ß-catenin translocation capability and the ALP activation activities of the target compounds were tested and calculated. The EC50 value of the ALP activation activity of 6-(4-chlorobenzyl)-3-{4-[(2-dimethylamino)-2- oxoethoxy]phenyl}-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one (6b) was 11.283 µM. The molecular docking results have showed that the target compounds would be GSK-3 inhibitors. CONCLUSION: Based on the results of the biological activity test, the target compounds have exhibited the ß-catenin translocation capability and the ALP activation activity.


Assuntos
Fosfatase Alcalina/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Triazinas/farmacologia , beta Catenina/metabolismo , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Triazinas/síntese química , Triazinas/química
16.
Arch Physiol Biochem ; 124(2): 139-148, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28868937

RESUMO

CONTEXT: Cigarette smoking is considered to be a major risk factor for the development of diabetes and cardiovascular disease. Oestrogen-progestin combined oral contraceptive (COC) use has been associated with adverse cardiometabolic events. OBJECTIVE: We hypothesized that nicotine would ameliorate insulin resistance (IR) that is accompanied by decreased cardiac glycogen synthase kinase-3 (GSK-3) and plasminogen activator inhibitor-1 (PAI-1). METHODS: Female Wistar rats received (po) low-(0.1 mg/kg) or high-nicotine (1.0 mg/kg) with or without COC containing 5.0 µg levonorgestrel plus 1.0 µg ethinylestradiol daily for 8 weeks. RESULTS: Data showed that COC treatment or nicotine exposure led to IR, glucose deregulation, atherogenic dyslipidemia, increased corticosterone, aldosterone, cardiac and circulating GSK-3 values and PAI-1. However, these effects with the exception of corticosterone and aldosterone were ameliorated in COC + nicotine-exposed rats. CONCLUSION: Amelioration of IR induced by COC treatment is accompanied by decreased circulating PAI-1, cardiac PAI-1 and GSK-3 instead of circulating aldosterone and corticosterone.


Assuntos
Anticoncepcionais Orais Combinados/efeitos adversos , Etinilestradiol/efeitos adversos , Quinase 3 da Glicogênio Sintase/metabolismo , Coração/efeitos dos fármacos , Resistência à Insulina , Levanogestrel/efeitos adversos , Nicotina/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Administração Oral , Aldosterona/sangue , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Anticoncepcionais Orais Combinados/antagonistas & inibidores , Corticosterona/sangue , Relação Dose-Resposta a Droga , Etinilestradiol/antagonistas & inibidores , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/sangue , Insulina/sangue , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Levanogestrel/antagonistas & inibidores , Miocárdio/enzimologia , Miocárdio/metabolismo , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/química , Estado Pré-Diabético/induzido quimicamente , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Estado Pré-Diabético/prevenção & controle , Distribuição Aleatória , Ratos Wistar
17.
PLoS One ; 12(11): e0178881, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29161257

RESUMO

Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro-neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator). Here, we show that the combined action of CHIR99021 and forskolin converted malignant glioma into fully differentiated neurons with no malignant characteristics; inhibited the proliferation of malignant glioma; and significantly down-regulated gene ontology and gene expression profiles related to cell division, gliogenesis, and angiogenesis in small molecule-induced neurons. In vivo, the combined action of CHIR99021 and forskolin markedly delayed neurological deficits and significantly reduced the tumor volume. We suggest that reprogramming technology may be a potential treatment strategy replacing the therapeutic paradigm of traditional treatment of malignant glioma, and a combination molecule comprising a GSK3 inhibitor and a cAMP inducer could be the next generation of anticancer drugs.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Quinase 3 da Glicogênio Sintase/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colforsina/administração & dosagem , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/patologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Imagem Óptica , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Biol Chem ; 292(50): 20785-20798, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29070680

RESUMO

A key feature of acute myocardial infarction (AMI) is an alteration in cardiac architecture. Signaling events that result in the inhibition of glycogen synthase kinase-3 (GSK-3)ß represent an adaptive response that might limit the extent of adverse remodeling in the aftermath of AMI. Here, we report that an allosteric inhibitor of GSK-3ß, 4-benzyl-2-(naphthalene-1-yl)-1,2,4-thiadiazolidine-3,5-dione (NP12), lessens the magnitude of adverse myocardial remodeling and promotes angiogenesis. Male and female mice 8-10 weeks old were grouped (six animals in each group) into sham surgery (sham group), left anterior descending (LAD) ligation of the coronary artery followed by intramyocardial PBS injections (control group), and LAD ligation followed by NP12 administration (NP12 group). After 7 and 14 days, the extents of fibrosis and integrity of blood vessels were determined. Intramyocardial administration of NP12 increased phosphorylation of GSK-3ß, reduced fibrosis, and restored diastolic function in the mice that had experienced an AMI. Morphometric analyses revealed increased CD31+ and Ki67+ vascular structures and decreased apoptosis in these mice. NP12 administration mediated proliferation of reparative cells in the AMI hearts. In a time-course analysis, Wnt3a and NP12 stabilized ß-catenin and increased expression of both Nanog and VEGFR2. Moreover, NP12 increased the expression of ß-catenin and Nanog in myocardium from AMI mice. Finally, loss- and gain-of-function experiments indicated that the NP12-mediated benefit is, in part, Nanog-specific. These findings indicate that NP12 reduces fibrosis, reestablishes coronary blood flow, and improves ventricular function following an AMI. We conclude that NP12 might be useful for limiting ventricular remodeling after an AMI.


Assuntos
Indutores da Angiogênese/uso terapêutico , Remodelamento Atrial/efeitos dos fármacos , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Infarto do Miocárdio/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tiadiazóis/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Indutores da Angiogênese/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aorta/cirurgia , Apoptose/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Técnicas In Vitro , Ligadura , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Tiadiazóis/farmacologia
19.
Neurosci Bull ; 33(6): 641-652, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28828584

RESUMO

Neurons grow multiple axons after treatment with glycogen synthase kinase-3 (GSK-3) inhibitors. However, whether they are electrically active is not known. Here, we examined the role of multiple axons as electrophysiological components during neuronal firing. Combining pharmacological, immunofluorescence, and electrophysiological methods, we found that more neurons had multiple axon initial segments (AISs) after inhibition of GSK-3 activity with SB415286. The multiple AISs induced by GSK-3 inhibition were enriched with voltage-gated sodium channels. The depolarization rate of the multiple-AIS neurons was increased, but their action potential threshold and half-width were normal. By calculating derivatives of the action-potential rising phase, an extra d2 V/dt 2 peak from the extra AIS was distinguished; this indicated that the extra AIS fired ahead of the soma and increased the rate of depolarization. Our study demonstrates that the multiple axons induced by GSK-3 inhibition have AIS structures that are electrically active, and provides insight for axon and AIS studies.


Assuntos
Segmento Inicial do Axônio , Axônios , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hipocampo/citologia , Neurônios , Inibidores de Proteínas Quinases/farmacologia , Potenciais de Ação/fisiologia , Aminofenóis/farmacologia , Animais , Animais Recém-Nascidos , Segmento Inicial do Axônio/efeitos dos fármacos , Axônios/efeitos dos fármacos , Maleimidas/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Oxid Med Cell Longev ; 2017: 2487297, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28814986

RESUMO

In childhood acute lymphoblastic leukemia, treatment failure is associated with resistance to glucocorticoid agents. Resistance to this class of drugs represents one of the strongest indicators of poor clinical outcome. We show that leukemic cells, which are resistant to the glucocorticoid drug methylprednisolone, display a higher demand of glucose associated with a deregulation of metabolic pathways, in comparison to sensitive cells. Interestingly, a combinatorial treatment of glucocorticoid and the glucose analog 2-deoxy-D-glucose displayed a synergistic effect in methylprednisolone-resistant cells, in an oxygen tension-independent manner. Unlike solid tumors, where 2-deoxy-D-glucose promotes inhibition of glycolysis by hexokinase II exclusively under hypoxic conditions, we were able to show that the antileukemic effects of 2-deoxy-D-glucose are far more complex in leukemia. We demonstrate a hexokinase II-independent cell viability decrease and apoptosis induction of the glucose analog in leukemia. Additionally, due to the structural similarity of 2-deoxy-D-glucose with mannose, we could confirm that the mechanism by which 2-deoxy-D-glucose predominantly acts in leukemia is via modification in N-linked glycosylation, leading to endoplasmic reticulum stress and consequently induction of the unfolded protein response.


Assuntos
Apoptose/efeitos dos fármacos , Desoxiglucose/toxicidade , Oxigênio/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glucose/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicólise/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Hexoquinase/antagonistas & inibidores , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Metilprednisolona/farmacologia , Nitrogênio/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/toxicidade , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
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