scholarly journals Antitumor Activity of Nitazoxanide against Colon Cancers: Molecular Docking and Experimental Studies Based on Wnt/β-Catenin Signaling Inhibition

2021 ◽  
Vol 22 (10) ◽  
pp. 5213
Author(s):  
Noha M. Abd El-Fadeal ◽  
Mohamed S. Nafie ◽  
Mohammed K. El-kherbetawy ◽  
Amr El-mistekawy ◽  
Hala M. F. Mohammad ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cytotoxic Effect ◽  
Glycogen Synthase ◽  
Experimental Studies ◽  
Nuclear Antigen ◽  
Normal Colon ◽  
Colon Cells ◽  
Hct 116 ◽  
Gsk 3Β

In colon cancer, wingless (Wnt)/β-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/β-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and β-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/β-catenin/glycogen synthase kinase-3β (GSK-3β) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/β-catenin/GSK-3β signaling.

scholarly journals Glycogen Synthase Kinase 3β Is Positively Regulated by Protein Kinase Cζ-Mediated Phosphorylation Induced by Wnt Agonists

2015 ◽  
Vol 36 (5) ◽  
pp. 731-741 ◽  
Author(s):  
Nydia Tejeda-Muñoz ◽  
Héctor González-Aguilar ◽  
Paula Santoyo-Ramos ◽  
M. Cristina Castañeda-Patlán ◽  
Martha Robles-Flores
Keyword(s):  
Protein Kinase ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Resting Cells ◽  
Malignant Cells ◽  
Glycogen Synthase Kinase 3Β ◽  
Colon Cells ◽  
Basal Activity ◽  
Gsk 3Β

The molecular events that drive Wnt-induced regulation of glycogen synthase kinase 3β (GSK-3β) activity are poorly defined. In this study, we found that protein kinase Cζ (PKCζ) and GSK-3β interact mainly in colon cancer cells. Wnt stimulation induced a rapid GSK-3β redistribution from the cytoplasm to the nuclei in malignant cells and a transient PKC-mediated phosphorylation of GSK-3β at a different site from serine 9. In addition, while Wnt treatment induced a decrease in PKC-mediated phosphorylation of GSK-3β in nonmalignant cells, in malignant cells, this phosphorylation was increased. Pharmacological inhibition and small interfering RNA (siRNA)-mediated silencing of PKCζ abolished all of these effects, but unexpectedly, it also abolished the constitutive basal activity of GSK-3β.In vitroactivity assays demonstrated that GSK-3β phosphorylation mediated by PKCζ enhanced GSK-3β activity. We mapped Ser147 of GSK-3β as the site phosphorylated by PKCζ, i.e., its mutation into alanine abolished GSK-3β activity, resulting in β-catenin stabilization and increased transcriptional activity, whereas phosphomimetic replacement of Ser147 by glutamic acid maintained GSK-3β basal activity. Thus, we found that PKCζ phosphorylates GSK-3β at Ser147 to maintain its constitutive activity in resting cells and that Wnt stimulation modifies the phosphorylation of Ser147 to regulate GSK-3β activity in opposite manners in normal and malignant colon cells.

scholarly journals Characterization of the Interaction between Latency-Associated Nuclear Antigen and Glycogen Synthase Kinase 3β

2009 ◽  
Vol 83 (12) ◽  
pp. 6312-6317 ◽  
Author(s):  
Thilo Hagen
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Nuclear Antigen ◽  
Glycogen Synthase Kinase 3Β ◽  
Intact Cells ◽  
Von Hippel Lindau ◽  
Gsk 3Β ◽  
The Stability

ABSTRACT The latency-associated nuclear antigen (LANA) of Karposi's sarcoma-associated herpesvirus has been reported to interact with glycogen synthase kinase 3β (GSK-3β) and regulate its activity, leading to inhibition of GSK-3-dependent β-catenin degradation. In this study, the interaction between LANA and GSK-3β was characterized further. LANA was found to interact with GSK-3β in vitro as well as in intact cells. However, LANA did not regulate GSK-3β kinase activity and LANA-induced upregulation of β-catenin was GSK-3β independent. LANA did not regulate the stability of β-catenin or of its reported interaction partners p53 and von Hippel-Lindau protein. Additional targets of LANA are likely to mediate its malignancy-promoting function.

scholarly journals Medicinal Plants in the Prevention and Treatment of Colon Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-51 ◽  
Author(s):  
Paola Aiello ◽  
Maedeh Sharghi ◽  
Shabnam Malekpour Mansourkhani ◽  
Azam Pourabbasi Ardekan ◽  
Leila Jouybari ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Medicinal Plants ◽  
English Language ◽  
Experimental Studies ◽  
Cyclin B1 ◽  
Nuclear Antigen ◽  
Underlying Mechanisms

The standard treatment for cancer is generally based on using cytotoxic drugs, radiotherapy, chemotherapy, and surgery. However, the use of traditional treatments has received attention in recent years. The aim of the present work was to provide an overview of medicinal plants effective on colon cancer with special emphasis on bioactive components and underlying mechanisms of action. Various literature databases, including Web of Science, PubMed, and Scopus, were used and English language articles were considered. Based on literature search, 172 experimental studies and 71 clinical cases on 190 plants were included. The results indicate that grape, soybean, green tea, garlic, olive, and pomegranate are the most effective plants against colon cancer. In these studies, fruits, seeds, leaves, and plant roots were used for in vitro and in vivo models. Various anticolon cancer mechanisms of these medicinal plants include induction of superoxide dismutase, reduction of DNA oxidation, induction of apoptosis by inducing a cell cycle arrest in S phase, reducing the expression of PI3K, P-Akt protein, and MMP as well; reduction of antiapoptotic Bcl-2 and Bcl-xL proteins, and decrease of proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin B1 and cyclin E. Plant compounds also increase both the expression of the cell cycle inhibitors p53, p21, and p27, and the BAD, Bax, caspase 3, caspase 7, caspase 8, and caspase 9 proteins levels. In fact, purification of herbal compounds and demonstration of their efficacy in appropriate in vivo models, as well as clinical studies, may lead to alternative and effective ways of controlling and treating colon cancer.

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

scholarly journals Ultrasound-enhanced biosynthesis of uniform ZnO nanorice using Swietenia macrophylla seed extract and its in vitro anticancer activity

2021 ◽  
Vol 10 (1) ◽  
pp. 572-585
Author(s):  
Darren Yi Sern Low ◽  
Camille Keisha Mahendra ◽  
Janarthanan Supramaniam ◽  
Loh Teng Hern Tan ◽  
Learn Han Lee ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Hexagonal Wurtzite Structure ◽  
Colon Cancer Cells ◽  
Swietenia Macrophylla ◽  
Zno Nps ◽  
Human Colon Cancer ◽  
Hct 116

Abstract In this study, ultrasonically driven biosynthesis of zinc oxide nanoparticles (ZnO NPs) using Swietenia macrophylla seed ethyl acetate fraction (SMEAF) has been reported. X-ray powder diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR) analyses confirmed the presence of a pure hexagonal wurtzite structure of ZnO. Field emission scanning electron microscope images revealed the formation of uniquely identifiable uniform rice-shaped biologically synthesized ZnOSMEAF particles. The particle sizes of the biosynthesized NPs ranged from 262 to 311 nm. The underlying mechanisms for the biosynthesis of ZnOSMEAF under ultrasound have been proposed based on FTIR and XRD results. The anticancer activity of the as-prepared ZnOSMEAF was investigated against HCT-116 human colon cancer cell lines via methyl thiazolyl tetrazolium assay. ZnOSMEAF exhibited significant anticancer activity against colon cancer cells with higher potency than ZnO particles prepared using the chemical method and SMEAF alone. Exposure of HCT-116 colon cancer cells to ZnOSMEAF promoted a remarkable reduction in cell viability in all the tested concentrations. This study suggests that green sonochemically induced ZnO NPs using medicinal plant extract could be a potential anticancer agent for biomedical applications.

scholarly journals Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5391
Author(s):  
Zheng Liu ◽  
Ming Bian ◽  
Qian-Qian Ma ◽  
Zhuo Zhang ◽  
Huan-Huan Du ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
In Vivo Studies ◽  
Neuroprotective Effects ◽  
Β Amyloid ◽  
Gsk 3Β

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.

scholarly journals The Sirtuin 3 Expression Profile Is Associated with Pathological and Clinical Outcomes in Colon Cancer Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Chunyuan Liu ◽  
Zonghai Huang ◽  
Hong Jiang ◽  
Fujun Shi
Keyword(s):  
Colon Cancer ◽  
Clinical Outcomes ◽  
Biological Behavior ◽  
Sirtuin 3 ◽  
Cancer Specific Survival ◽  
Colon Cells ◽  
Tumor Stages ◽  
Colon Cell ◽  
Sirt3 Expression

Aim.To investigate the correlation between Sirtuin 3 (SIRT3) expression and the clinical outcome of patients with colon cancer.Methods. The tumor specimens from 127 patients with colon cancer were obtained for SIRT3 immunohistochemical staining. Patients were followed up. Inin vitrostudy, SIRT3 gene was inhibited to observe the effects of SIRT3 on the biological behavior of cultured colon cells.Results. The SIRT3 expression level was found to be significantly associated with the lymph node metastasis (P<0.001) and tumor stages (P<0.001). The colon cancer-specific survival was 64.6% among patients with high SIRT3 expressions and 88.6% among patients with low SIRT3 expressions (log-rankP=0.016). The overall survival was 80.2% among patients with low SIRT3 expressions and 55.9% among patients with high SIRT3 expressions (log-rankP=0.002).In vitrostudy showed that silencing of SIRT3 gene inhibited the proliferation, invasion, and cells migration but increased the apoptosis in the cultured colon cell lines.Conclusion. This study provides evidence supporting that SIRT3 is closely associated with the clinical outcomes of colon cancer. SIRT3 may be considered as a marker for colon cancer.

scholarly journals Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer’s Disease

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1307 ◽  
Author(s):  
Eliška Kohelová ◽  
Rozálie Peřinová ◽  
Negar Maafi ◽  
Jan Korábečný ◽  
Daniela Hulcová ◽  
...  
Keyword(s):  
Active Sites ◽  
Glycogen Synthase ◽  
Binding Modes ◽  
Structural Determinants ◽  
Inhibitory Potential ◽  
Gsk 3Β ◽  
Inhibition Potency ◽  
Derivatives Of ◽  
In Vitro Data

Twelve derivatives 1a–1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds’ plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.

scholarly journals RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Jikui Sun ◽  
Quanfeng Ma ◽  
Banban Li ◽  
Chen Wang ◽  
Lidong Mo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Inhibitory Effect ◽  
Who Grade ◽  
Pathway Network ◽  
Mechanistic Investigation ◽  
Signaling Axis ◽  
Gsk 3Β

Abstract Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

Cytotoxic Effect of Allium cepa L. Extract on Human colon Cancer (WiDr) Cells: In Vitro Study

2019 ◽  
Vol 12 (7) ◽  
pp. 3483
Author(s):  
Amaq Fadholly ◽  
Arif N. M. Ansori ◽  
Shara Jayanti ◽  
Annise Proboningrat ◽  
Muhammad K. J. Kusala ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Allium Cepa ◽  
Cytotoxic Effect ◽  
In Vitro Study ◽  
Human Colon ◽  
Vitro Study ◽  
Human Colon Cancer ◽  
Allium Cepa L
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