RESUMO
As a "silent threat," Alzheimer's disease (AD) is quickly rising to the top of the list of costly and troublesome diseases facing humanity. It is growing to be one of the most troublesome and expensive conditions, with annual health care costs higher than those of cancer and comparable to those of cardiovascular disorders. One of the main pathogenic characteristics of AD is the deficiency of the neurotransmitter acetylcholine (ACh) which plays a vital role in memory, learning, and attention. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in hydrolyzing ACh. Consequently, a frequent therapy approach for AD is the suppression of AChE and BChE to improve cholinergic neurotransmission and reduce cognitive symptoms. The accumulation of amyloid plaques (Aß) is a primary factor contributing to neurodegenerative diseases, particularly AD. Glycogen synthase kinase-3ß (GSK3-ß) is regarded as a pivotal player in the pathophysiology of AD since dysregulation of this kinase affects all major hallmarks of the disease, such as tau phosphorylation, Aß aggregation, memory, neurogenesis, and synaptic function. One of the most challenging and risky issues in modern medicinal chemistry is the urgent and ongoing need for the study and development of effective therapeutic candidates for the treatment of AD. A significant class of heterocyclic molecules that can target the complex and multifactorial pathogenesis of AD are fused thiophene derivatives. The goal of the current review is to demonstrate the advancements made in fused thiophene derivatives' anti-AD activity. It also covers their mechanisms of action and studies of the structure-activity relationships in addition to the compilation of significant synthetic routes for fused thiophene derivatives with anti-AD potential. This review is intended to stimulate new ideas in the search for more rationale designs of derivatives based on fused thiophene, hoping to be more potent in treating AD.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Butirilcolinesterase , Acetilcolinesterase , Quinase 3 da Glicogênio Sintase/uso terapêutico , Monoaminoxidase , Acetilcolina , Peptídeos beta-Amiloides , Glicogênio Sintase Quinase 3 betaRESUMO
The intricate molecular pathways governing cancer development and progression have spurred intensive investigations into novel therapeutic targets. Glycogen Synthase Kinase-3 (GSK3), a complex serine/threonine kinase, has emerged as a key player with intricate roles in various cellular processes, including cell proliferation, differentiation, apoptosis, and metabolism. Harnessing GSK3 inhibitors as potential candidates for cancer therapy has garnered significant interest due to their ability to modulate key signalling pathways that drive oncogenesis. The review encompasses a thorough examination of the molecular mechanisms underlying GSK3's involvement in cancer progression, shedding light on its interaction with critical pathways such as Wnt/ß-catenin, PI3K/AKT, and NF-κB. Through these interactions, GSK3 exerts influence over tumour growth, invasion, angiogenesis, and metastasis, rendering it an attractive target for therapeutic intervention. The discussion includes preclinical and clinical studies, showcasing the inhibitors efficacy across a spectrum of cancer types, including pancreatic, ovarian, lung, and other malignancies. Insights from recent studies highlight the potential synergistic effects of combining GSK3 inhibitors with conventional chemotherapeutic agents or targeted therapies, opening avenues for innovative combinatorial approaches. This review provides a comprehensive overview of the current state of research surrounding GSK3 inhibitors as promising agents for cancer treatment.
Assuntos
Quinase 3 da Glicogênio Sintase , Neoplasias , Humanos , Quinase 3 da Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , NF-kappa B/metabolismoRESUMO
BACKGROUND: The association between diabetes mellitus (DM) and the increased risk and progression of cholangiocarcinoma (CCA) has been reported with unclear underlying mechanisms. Previous studies showed that γ-aminobutyric acid (GABA) B2 receptor (GABBR2) was upregulated in CCA cells cultured in high glucose (HG) conditions. Roles of GABA receptors in CCA progression have also been studied, but their association with DM and hyperglycemia in CCA remains unclarified. AIM: To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target. METHODS: CCA cells, KKU-055 and KKU-213A, were cultured in Dulbecco Modified Eagle's Medium supplemented with 5.6 mmol/L (normal glucose, NG) or 25 mmol/L (HG) glucose and assigned as NG and HG cells, respectively. GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot. Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence. GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry, and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis. Effects of baclofen, a GABA-B receptor agonist, on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays. Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment, and the candidate signaling molecules were validated using the public transcriptomic data and western blot. RESULTS: GABBR2 expression in CCA cells was induced by HG in a dose- and time-dependent manner. CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia (P < 0.01). High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors (P < 0.05). HG cells of both tested CCA cell lines were more sensitive to baclofen treatment. Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions (P < 0.05). Phospho-kinase arrays suggested glycogen synthase kinase 3 (GSK3), ß-catenin, and the signal transducer and activator of transcription 3 (STAT3) as candidate signaling molecules under the regulation of GABBR2, which were verified in NG and HG cells of the individual CCA cell lines. Cyclin D1 and c-Myc, the common downstream targets of GSK3/ß-catenin and STAT3 involving cell proliferation, were accordingly downregulated after baclofen treatment. CONCLUSION: GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Diabetes Mellitus , Hiperglicemia , Humanos , beta Catenina/metabolismo , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Baclofeno/farmacologia , Baclofeno/uso terapêutico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Proliferação de Células , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/patologia , Glucose/farmacologia , Glucose/uso terapêutico , Linhagem Celular TumoralRESUMO
HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain-derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-ß). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 + lymphocyte activation (CD38 + HLADR +). Alzheimer's Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/ß), Aß38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (± 8.35) years and the median CD4 + T-cell count was 498 (IQR: 389-651) cells/µL. Biomarker concentrations between groups did not differ at baseline. However, both groups' blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.
Assuntos
Infecções por HIV , HIV , Humanos , Adulto , Pessoa de Meia-Idade , Lítio/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo , Dopamina , Quinase 3 da Glicogênio Sintase/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , BiomarcadoresRESUMO
AIMS: Inhibitors of SGLT2 (SGLT2i) have shown a positive impact in patients with chronic heart failure and reduced ejection fraction (HFrEF). Nonetheless, the direct effects of SGLT2i on cardiac cells and how their association with main drugs used for HFrEF affect the behaviour and signalling pathways of myocardial fibroblasts are still unknown. We aimed to determine the effects of dapagliflozin alone and in combination with sacubitril/valsartan (LCZ696) or spironolactone on the function of myocardial fibroblasts of patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Myocardial fibroblasts isolated from HFrEF patients (n = 5) were treated with dapagliflozin alone (1 nM-1 µM) or combined with LCZ696 (100 nM) or spironolactone (100 nM). The migratory rate was determined by wound-healing scratch assay. Expression of heart failure (HF) markers and signalling pathways activation were analysed with multiplexed protein array. Commercially available cardiac fibroblasts from healthy donors were used as Control (n = 4). Fibroblasts from HFrEF show higher migratory rate compared with control (P = 0.0036), and increased expression of HF markers [fold-change (Log2): COL1A1-1.3; IL-1b-1.9; IL-6-1.7; FN1-2.9 (P < 0.05)]. Dapagliflozin slowed the migration rate of HFrEF fibroblasts in a dose-dependent manner and markedly decreased the expression of IL-1ß, IL-6, MMP3, MMP9, GAL3, and FN1. SGLT2i had no effect on control fibroblasts. These effects were associated with decreased phosphorylation of AKT/GSK3 and PYK2 kinases and the signal transducer and activator of transcription (STAT). A combination of dapagliflozin + LCZ696 further decreased fibroblast migration, although it did not have a significant effect on the regulation of signalling pathways and the expression of biomarkers induced by SGLT2 inhibition alone. In contrast, the combination of dapagliflozin + spironolactone did not change the migration rate of fibroblast but significantly altered SGLT2i responses on MMP9, GAL3, and IL-1b expression, in association with increased phosphorylation of the kinases AKT/GSK3 and ERK1/2. CONCLUSIONS: SGLT2i, LCZ696, and spironolactone modulate the function of isolated myocardial fibroblasts from HFrEF patients through the activation of different signalling pathways. The combination of SGLT2i + LCZ696 shows an additive effect on migration, while spironolactone modifies the signalling pathways activated by SGLT2i and its beneficial effects of biomarkers of heart failure.
Assuntos
Insuficiência Cardíaca , Humanos , Espironolactona/farmacologia , Metaloproteinase 9 da Matriz/farmacologia , Metaloproteinase 9 da Matriz/uso terapêutico , Transportador 2 de Glucose-Sódio/farmacologia , Transportador 2 de Glucose-Sódio/uso terapêutico , Volume Sistólico , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Interleucina-6 , Proteínas Proto-Oncogênicas c-akt/farmacologia , Proteínas Proto-Oncogênicas c-akt/uso terapêutico , Valsartana/uso terapêutico , Fibroblastos , BiomarcadoresRESUMO
BACKGROUND/AIM: Prostate cancer (PCa) is one of the most common malignancies in adult men. LQB-118 is a pterocarpanquinone with antitumor activity toward prostate cancer cells. It inhibits cell proliferation by down-regulating cyclins D1 and B1 and up-regulating p21. However, the effects of LQB-118 on PCa cell migration are still unclear. Herein, the LQB-118 effects on PCa metastatic cell migration/invasion and its mechanism of action were evaluated. MATERIALS AND METHODS: PC3 cells were treated with LQB-118 or Paclitaxel (PTX), and cell migration (wound healing and Boyden chamber assays) and invasion (matrigel assay) were determined. The LQB-118 mechanisms were evaluated by αVßIII protein expression (flow cytometry), protein phosphorylation (Western blot), and mRNA expression (qPCR). RESULTS: LQB-118 impaired PCa cell migration and invasion, down-regulated Akt phosphorylation, and also reduced GSK3ß phosphorylation, through a FAK-independent pathway. Also, it was observed that LQB-118 controlled the invasiveness behavior by reducing matrix metalloproteinase-9 (MMP-9) and up-regulating reversion-inducing cysteine rich protein with Kazal motifs (Reck) mRNA levels. Interestingly, LQB-118 increased integrin αvßIII expression, but this effect was not related to its activation, since the cell adhesion ability was reduced after LQB-118 treatment. CONCLUSION: These data highlight novel LQB-118 mechanisms in prostate cancer cells. LQB-118 acts as a negative regulator of the Akt/GSK3 signaling pathway and can modulate PCa cell proliferation, death, and migration/invasion. The results also support the use of LQB-118 for the treatment of metastatic PCa, alone or combined with another chemotherapeutic agent, due to its demonstrated pleiotropic activities.
Assuntos
Metaloproteinase 9 da Matriz , Neoplasias da Próstata , Humanos , Masculino , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Expressão Gênica , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Ligadas por GPI/efeitos dos fármacos , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA MensageiroRESUMO
BACKGROUND: Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. METHODS: A quantitative high-throughput drug screening of 4,991 compounds was performed on two ACC cell lines, SW13 and NCI-H295R, based on antiproliferative effect and caspase-3/7 activity. The top candidate drugs were pairwise combined to identify the most potent combinations. The synergistic efficacy of the selected inhibitors was tested on tumorigenic phenotypes, such as cell proliferation, migration, invasion, spheroid formation, and clonogenicity, with appropriate mechanistic validation by cell cycle and apoptotic assays and protein expression of the involved molecules. We tested the efficacy of the drug combination in mice with luciferase-tagged human ACC xenografts. To study the mRNA expression of target molecules in ACC and their clinical correlations, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas. RESULTS: We chose the maternal embryonic leucine zipper kinase (MELK) inhibitor (OTS167) and cyclin-dependent kinase (CDK) inhibitor (RGB-286638) because of their potent synergy from the pairwise drug combination matrices derived from the top 30 single drugs. Multiple publicly available databases demonstrated overexpression of MELK, CDK1/2, and partnering cyclins mRNA in ACC, which were independently associated with mortality and other adverse clinical features. The drug combination demonstrated a synergistic antiproliferative effect on ACC cells. Compared to the single-agent treatment groups, the combination treatment increased G2/M arrest, caspase-dependent apoptosis, reduced cyclins A2, B1, B2, and E2 expression, and decreased cell migration and invasion with reduced vimentin. Moreover, the combination effectively decreased Foxhead Box M1, Axin2, glycogen synthase kinase 3-beta, and ß-catenin. A reduction in p-stathmin from the combination treatment destabilized microtubule assembly by tubulin depolymerization. The drug combination treatment in mice with human ACC xenografts resulted in a significantly lower tumor burden than those treated with single-agents and vehicle control groups. CONCLUSIONS: Our preclinical study revealed a novel synergistic combination of OTS167 and RGB-286638 in ACC that effectively targets multiple molecules associated with ACC aggressiveness. A phase Ib/II clinical trial in patients with advanced ACC is therefore warranted.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Animais , Apoptose , Caspase 3 , Linhagem Celular Tumoral , Proliferação de Células , Quinases Ciclina-Dependentes , Ciclinas , Pontos de Checagem da Fase G2 do Ciclo Celular , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Humanos , Camundongos , Proteínas Serina-Treonina Quinases , Pirazóis , RNA Mensageiro , Estatmina , Tubulina (Proteína) , Ureia/análogos & derivados , Vimentina , beta CateninaRESUMO
Chemoresistance is a main obstacle for colorectal cancer treatment. In this study, we evaluated the effects and mechanisms of the WNT/ß-catenin signaling pathway on the chemoresistance of SW480 and SW620 colorectal cancer cells. The activity of ß-catenin was activated/inhibited by the small molecule compound GSK-3 inhibitor 6-bromo-indirubin-3'-oxime and the tankyrase inhibitor XAV939. The downstream target genes of the WNT/ß-catenin signaling pathway were screened using a cDNA microarray and bioinformatics analysis. Apoptosis induced by 5-Fu, cell cycle distribution and expression levels of WNT/ß-catenin/TCF12/caveolin-1 and multidrug resistance proteins were examed by flow cytometry and western blot after ß-catenin activation/inhibition and caveolin-1 overexpression/interference. The effect and mechanism of XAV939 on proliferation and apoptosis induced by 5-Fu in xenograft tumors of nude mice were evaluated by immunohistochemistry and TUNEL staining. 6-Bromo-indirubin-3'-oxime treatment increased ß-catenin expression by regulating GSK-3ß phosphorylation, accompanied by upregulation of TCF12, caveolin-1, P-gp, and MRP2 and downregulation of apoptosis induced by 5-Fu. Conversely, XAV939 treatment decreased ß-catenin expression by upregulating Axin, accompanied by downregulation of TCF12, Caveolin-1, P-gp, and MRP2 and upregulation of apoptosis induced by 5-Fu. The caveolin-1 gene was identified as an important downstream gene of the WNT/ß-catenin signaling pathway. Caveolin-1 overexpression upregulated ß-catenin expression, increased P-gp and MRP2 expression and decreased apoptosis induced by 5-Fu; conversely, caveolin-1 interference caused the opposite effects. In addition, in vivo experiments showed that XAV939 treatment reduced ß-catenin expression, increased apoptosis induced by 5-Fu and repressed xenograft tumor growth. Our findings suggested that inhibition of WNT/ß-catenin/TCF12/caveolin-1 provides a new promising therapeutic strategy for colorectal cancer treatment.
Assuntos
Neoplasias Colorretais , Tanquirases , Camundongos , Animais , Humanos , Tanquirases/genética , Tanquirases/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Proteína Axina/metabolismo , Proteína Axina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Caveolina 1/genética , Caveolina 1/metabolismo , Caveolina 1/farmacologia , Camundongos Nus , Glicogênio Sintase Quinase 3 beta/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Via de Sinalização Wnt , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Apoptose , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Oximas/farmacologiaRESUMO
Differentiation therapy using all-trans retinoic acid (ATRA) is well established for the treatment of acute promyelocytic leukemia (APL). Several attempts have been made to treat non-APL acute myeloid leukemia (AML) patients by employing differentiation inducers, such as hypomethylating agents and low-dose cytarabine, with encouraging results. In the present review, I focus on other possible differentiation inducers: kinase inhibitors and interferons (IFNs). A number of kinase inhibitors have been reported to induce differentiation, including CDK inhibitors, GSK3 inhibitors, Akt inhibitors, p38 MAPK inhibitors, Src family kinase inhibitors, Syk inhibitors, mTOR inhibitors, and HSP90 inhibitors. Other powerful inducers are IFNs, which were reported to enhance differentiation with ATRA. Although clinical trials for these kinase modulators remain scarce, their mechanisms of action have been, at least partly, clarified. The Raf/MEK/ERK MAPK pathway and the RARα downstream are affected by many of the kinase inhibitors and IFNs and seem to play a pivotal role for the induction of myeloid differentiation. Further clarification of the mechanisms, as well as the establishment of efficient combination therapies with the kinase inhibitors or IFNs, may lead to the development of effective therapeutic strategies for AML.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Antineoplásicos/uso terapêutico , Diferenciação Celular , Quinase 3 da Glicogênio Sintase/uso terapêutico , Humanos , Interferons/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Tretinoína/farmacologia , Tretinoína/uso terapêuticoRESUMO
BACKGROUND: Induction of acquired drug resistance occurs frequently with cisplatin-based therapy for non-small cell lung cancer (NSCLC). As recent studies have demonstrated that deregulation of microRNAs (miRNAs) is associated with drug resistance in cancers, correcting the deregulation of miRNAs represents a promising strategy to reverse acquired resistance in NSCLC. OBJECTIVES: This study investigated the functional role of miR-15b in cisplatin resistance in NSCLC. MATERIAL AND METHODS: Cisplatin-resistant PC9 and A549 NSCLC cell lines (PC9-R and A549-R) were established through long-term exposure to cisplatin. Differences in miR-15b expression between cisplatin-resistant NSCLC cell lines and their parental cell lines were identified through quantitative real-time polymerase chain reaction (qRT-PCR). The effect of anti-miR-15b on the sensitivity of PC9-R and A549-R to cisplatin-induced cytotoxicity was evaluated using Cell Counting Kit-8 (CCK-8) assays. Regulation of GSK-3ß by miR-15b was confirmed with luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) were measured using flow cytometry analysis. RESULTS: In PC9-R and A549-R cells, miR-15b was significantly overexpressed. However, knockdown of miR-15b clearly reduced cisplatin resistance in PC9-R and A549-R cells. Researching the mechanism, we proved that GSK-3ß was the target of miR-15b. Knockdown of miR-15b significantly increased the expression GSK-3ß and thus promoted the degradation of MCL-1, which is a key anti-apoptosis protein. As a result, anti-miR-15b expanded the cisplatin-induced apoptosis in cisplatin-resistant NSCLC cells. CONCLUSIONS: Knockdown of miR-15b partially reversed cisplatin resistance in NSCLC cells through the GSK-3ß/MCL-1 pathway.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/uso terapêuticoRESUMO
The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin's neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood-brain barrier, supporting medicarpin's protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-κB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and ß-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin's neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC50 around 5 ±1 (µM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC50 around 13 ± 2 (µM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating ß-catenin, which in turn decreases the expression/activation of p65NF-κB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain.
Assuntos
Lesões Encefálicas , Isquemia Encefálica , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/uso terapêutico , Caspase 3 , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pterocarpanos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , beta Catenina/uso terapêuticoRESUMO
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified because of its key role in the regulation of glycogen synthesis. However, it is now well-established that GSK-3 performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis. Aberrant GSK-3 activity has been associated with many human diseases, including cancer, highlighting its potential therapeutic relevance as a target for anticancer therapy. Recently, newly emerging data have demonstrated the pivotal role of GSK-3 in the anticancer immune response. In the last few years, many GSK-3 inhibitors have been developed, and some are currently being tested in clinical trials. This review will discuss preclinical and initial clinical results with GSK-3ß inhibitors, highlighting the potential importance of this target in cancer immunotherapy. As described in this review, GSK-3 inhibitors have been shown to have antitumor activity in a wide range of human cancer cells, and they may also contribute to promoting a more efficacious immune response against tumor target cells, thus showing a double therapeutic advantage.