scholarly journals Ginsenoside Compound K Induces Ros-Mediated Apoptosis and Autophagic Inhibition in Human Neuroblastoma Cells In Vitro and In Vivo

2019 ◽  
Vol 20 (17) ◽  
pp. 4279 ◽  
Author(s):  
Jung-Mi Oh ◽  
Eunhee Kim ◽  
Sungkun Chun
Keyword(s):  
Cell Death ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Autophagic Flux ◽  
Ros Scavenging ◽  
Compound K ◽  
Human Neuroblastoma ◽  
Ginsenoside Compound K

Autophagy can result in cellular adaptation, as well as cell survival or cell death. Modulation of autophagy is increasingly regarded as a promising cancer therapeutic approach. Ginsenoside compound K (CK), an active metabolite of ginsenosides isolated from Panax ginseng C.A. Meyer, has been identified to inhibit growth of cancer cell lines. However, the molecular mechanisms of CK effects on autophagy and neuroblastoma cell death have not yet been investigated. In the present study, CK inhibited neuroblastoma cell proliferation in vitro and in vivo. Treatment by CK also induced the accumulation of sub-G1 population, and caspase-dependent apoptosis in neuroblastoma cells. In addition, CK promotes autophagosome accumulation by inducing early-stage autophagy but inhibits autophagic flux by blocking of autophagosome and lysosome fusion, the step of late-stage autophagy. This effect of CK appears to be mediated through the induction of intracellular reactive oxygen species (ROS) and mitochondria membrane potential loss. Moreover, chloroquine, an autophagy flux inhibitor, further promoted CK-induced apoptosis, mitochondrial ROS induction, and mitochondria damage. Interestingly, those promoted phenomena were rescued by co-treatment with a ROS scavenging agent and an autophagy inducer. Taken together, our findings suggest that ginsenoside CK induced ROS-mediated apoptosis and autophagic flux inhibition, and the combination of CK with chloroquine, a pharmacological inhibitor of autophagy, may be a novel therapeutic potential for the treatment of neuroblastoma.

scholarly journals Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Diana Corallo ◽  
Fabio Pastorino ◽  
Marcella Pantile ◽  
Elena Mariotto ◽  
Federico Caicci ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Neuroblastoma Cell ◽  
Autophagic Flux ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Treatment Protocols

Abstract Background Despite reported advances, acquired resistance to tyrosine kinase inhibitors still represents a serious problem in successful cancer treatment. Among this class of drugs, ponatinib (PON) has been shown to have notable long-term efficacy, although its cytotoxicity might be hampered by autophagy. In this study, we examined the likelihood of PON resistance evolution in neuroblastoma and assessed the extent to which autophagy might provide survival advantages to tumor cells. Methods The effects of PON in inducing autophagy were determined both in vitro, using SK-N-BE(2), SH-SY5Y, and IMR-32 human neuroblastoma cell lines, and in vivo, using zebrafish and mouse models. Single and combined treatments with chloroquine (CQ)—a blocking agent of lysosomal metabolism and autophagic flux—and PON were conducted, and the effects on cell viability were determined using metabolic and immunohistochemical assays. The activation of the autophagic flux was analyzed through immunoblot and protein arrays, immunofluorescence, and transmission electron microscopy. Combination therapy with PON and CQ was tested in a clinically relevant neuroblastoma mouse model. Results Our results confirm that, in neuroblastoma cells and wild-type zebrafish embryos, PON induces the accumulation of autophagy vesicles—a sign of autophagy activation. Inhibition of autophagic flux by CQ restores the cytotoxic potential of PON, thus attributing to autophagy a cytoprotective nature. In mice, the use of CQ as adjuvant therapy significantly improves the anti-tumor effects obtained by PON, leading to ulterior reduction of tumor masses. Conclusions Together, these findings support the importance of autophagy monitoring in the treatment protocols that foresee PON administration, as this may predict drug resistance acquisition. The findings also establish the potential for combined use of CQ and PON, paving the way for their consideration in upcoming treatment protocols against neuroblastoma.

p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies

2020 ◽  
Vol 17 (2) ◽  
pp. 169-183 ◽  
Author(s):  
İrem Bozbey ◽  
Suat Sari ◽  
Emine Şalva ◽  
Didem Kart ◽  
Arzu Karakurt
Keyword(s):  
Molecular Modeling ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Cytotoxic Agents ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Modeling Studies ◽  
Broth Microdilution Method ◽  
Molecular Modeling Studies

Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 µM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells

1994 ◽  
Vol 14 (10) ◽  
pp. 6584-6596
Author(s):  
G Melino ◽  
M Annicchiarico-Petruzzelli ◽  
L Piredda ◽  
E Candi ◽  
V Gentile ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Changes ◽  
Tissue Transglutaminase ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Neuroblastoma Cell Line ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Transfected Cells ◽  
Protein Levels

In this report, we show that the overexpression of tissue transglutaminase (tTG) in the human neuroblastoma cell line SK-N-BE(2) renders these neural crest-derived cells highly susceptible to death by apoptosis. Cells transfected with a full-length tTG cDNA, under the control of a constitutive promoter, show a drastic reduction in proliferative capacity paralleled by a large increase in cell death rate. The dying tTG-transfected cells exhibit both cytoplasmic and nuclear changes characteristic of cells undergoing apoptosis. The tTG-transfected cells express high Bcl-2 protein levels as well as phenotypic neural cell adhesion molecule markers (NCAM and neurofilaments) of cells differentiating along the neuronal pathway. In keeping with these findings, transfection of neuroblastoma cells with an expression vector containing segments of the human tTG cDNA in antisense orientation resulted in a pronounced decrease of both spontaneous and retinoic acid (RA)-induced apoptosis. We also present evidence that (i) the apoptotic program of these neuroectodermal cells is strictly regulated by RA and (ii) cell death by apoptosis in the human neuroblastoma SK-N-BE(2) cells preferentially occurs in the substrate-adherent phenotype. For the first time, we report here a direct effect of tTG in the phenotypic maturation toward apoptosis. These results indicate that the tTG-dependent irreversible cross-linking of intracellular protein represents an important biochemical event in the induction of the structural changes featuring cells dying by apoptosis.

scholarly journals Intercellular transmission of a bacterial cytotoxic prion-like protein in mammalian cells

2019 ◽  
Author(s):  
Aida Revilla-García ◽  
Cristina Fernández ◽  
María Moreno-del Álamo ◽  
Vivian de los Ríos ◽  
Ina M. Vorberg ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Protein Quality ◽  
Horizontal Cell ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Neuroblastoma Cell Line ◽  
Human Neuroblastoma ◽  
Intracellular Traffic ◽  
First Time

AbstractRepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent to mitochondria impairment in human cells affected by neurodegeneration. To fulfil all the features of a prion-like protein, horizontal (intercellular) transmissibility remains to be demonstrated for RepA-WH1. Since this is experimentally intractable in bacteria, here we transiently expressed in a murine neuroblastoma cell line the soluble, barely cytotoxic RepA-WH1(WT) and assayed its response to co-incubation with in vitro assembled RepA-WH1(A31V) amyloid fibres. In parallel, cells releasing RepA-WH1(A31V) aggregates were co-cultured with human neuroblastoma cells expressing RepA-WH1(WT). Both the assembled fibres and the extracellular RepA-WH1(A31V) aggregates induce, in the cytosol of recipient cells, the formation of cytotoxic amyloid particles. Mass spectrometry analyses of the proteomes of both types of injured cells point to alterations in mitochondria, protein quality triage, signalling and intracellular traffic.Summary blurbThe horizontal, cell-to-cell spread of a bacterial prion-like protein is shown for the first time in mammalian cells. Amyloid cross-aggregation of distinct variants, and their associated toxicities, follow the same trend found in bacteria, underlining the universality of prion biology.

scholarly journals Neuroprotective Effect of Bergamot Juice in 6-OHDA-Induced SH-SY5Y Cell Death, an In Vitro Model of Parkinson’s Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 326 ◽  
Author(s):  
Nadia Ferlazzo ◽  
Santa Cirmi ◽  
Alessandro Maugeri ◽  
Caterina Russo ◽  
Giovanni Enrico Lombardo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Nuclear Translocation ◽  
Neuroprotective Effect ◽  
Neuroblastoma Cells ◽  
Specific Cell ◽  
Protective Effects ◽  
Human Neuroblastoma

Much evidence suggests that both oxidative stress and apoptosis play a key role in the pathogenesis of Parkinson’s disease (PD). The present study aims to evaluate the protective effect of bergamot juice (BJ) against 6-hydroxydopamine (6-OHDA)- or H2O2-induced cell death. Treatment of differentiated SH-SY5Y human neuroblastoma cells with 6-OHDA or H2O2 resulted in cell death that was significantly reduced by the pre-treatment with BJ. The protective effects of BJ seem to correlate with the reduction of intracellular reactive oxygen species and nitric oxide generation caused by 6-OHDA or H2O2. BJ also attenuated mitochondrial dysfunction, caspase-3 activation, imbalance of pro- and anti-apoptotic proteins, MAPKs activation and reduced NF-ĸB nuclear translocation evoked by neurotoxic agents. Additionally, BJ exhibited excellent antioxidant capability in cell-free assays. Collectively, our results suggest that BJ exerts neuroprotective effect through the interplay with specific cell targets and its antioxidant activity, making it worthy of consideration for the management of neurodegenerative diseases.

scholarly journals The Effects of Oleuropein on Different Clinically Types of Human Neuroblastoma Cells

Proceedings ◽  
2018 ◽  
Vol 2 (25) ◽  
pp. 1591
Author(s):  
Zekiye Altun ◽  
Efe Ozgur Serinan ◽  
Merve Tütüncü ◽  
Safiye Aktaş ◽  
Nur Olgun
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Model Organisms ◽  
Late Relapse ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma

Neuroblastoma is an embryonic tumor originating from the neural crest. It accounts for 8–10% of all childhood cancers. Although Cisplatin is used in neuroblastoma treatment, it has many side effects, such as ototoxicity, nephrotoxicity, and neurotoxicity. One herbal agent that has attracted attention in recent years is oleuropein (OLE), the active component of olive leaf. This component belongs to the polyphenol group and it has antioxidant, anti-microbial, anti-inflammatory, anti-hypertensive and anti-carcinogenic effects. It has beneficial effects against neurodegeneration in both culture cells and model organisms. Oleuropein has been shown to be increased apoptosis in SH-SY5Y neuroblastoma cell line in one study. Cisplatin (cis-diaminedichloroplatinum II (CDDP) is a widely used agent for the treatment of many different human cancers in childhood and adults with antimitotic and antineoplastic properties. CDDP is the most effective chemotherapeutic agent in specially treatment of neuroblastoma. Purpose of this study was to determine whether oleuropein and CDDP have possible anti-proliferative activity in different types of human neuroblastoma cells as representing different clinical features (bone marrow metastatic LAN-5 cells and treated with chemotherapy and beam therapy CHP-134 cells representing late relapse) investigated. Human bone marrow metastatic LAN-5 and treated with chemotherapy and beam therapy CHP-134 neuroblastoma cells representing late relapse were used in this study. The effects of OLE and CDDP on LAN-5 and CHP-134 neuroblastoma cell proliferation and apoptotic cell death was investigated using WST-1 cell proliferation and Annexin-V/PI flow cytometric assays. Oleuropein and CDDP have been shown to inhibit proliferation of LAN-5 and CHP-134 neuroblastoma cells. In further studies, it is planned to investigate different cell death mechanisms by using combination of oleuropein and cisplatin in different kind of human neuroblastoma cells.

scholarly journals A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

2017 ◽  
Vol 114 (6) ◽  
pp. E1009-E1017 ◽  
Author(s):  
Michele Perni ◽  
Céline Galvagnion ◽  
Alexander Maltsev ◽  
Georg Meisl ◽  
Martin B. D. Müller ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Natural Product ◽  
Self Assembly ◽  
Lipid Membranes ◽  
Neuroblastoma Cells ◽  
Lipid Vesicles ◽  
Human Neuroblastoma

The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

scholarly journals Inhibition of the SK-N-MC human neuroblastoma cell line in vivo and in vitro by a novel nutrient mixture

2013 ◽  
Vol 29 (5) ◽  
pp. 1714-1720 ◽  
Author(s):  
M. WAHEED ROOMI ◽  
TATIANA KALINOVSKY ◽  
NUSRATH W. ROOMI ◽  
ALEKSANDRA NIEDZWIECKI ◽  
MATTHIAS RATH
Keyword(s):  
Cell Line ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cell Line ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Human Neuroblastoma Cell Line

scholarly journals The The Effects of Centella asiatica Extract (CAE) on Methamphetamine-Induced Neurotoxicity via Human Neuroblastoma Cell Line

2021 ◽  
Vol 16 ◽  
pp. 1-9
Author(s):  
Mazatulikhma Mat Zain Mat Zain ◽  
Nursyamila Shamsuddin ◽  
Mohd Shihabuddin Ahmad Noorden
Keyword(s):  
Cell Death ◽  
Neuroblastoma Cell ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Centella Asiatica ◽  
Human Neuroblastoma Cell ◽  
Asiatic Acid ◽  
Dependent Manner ◽  
Human Neuroblastoma

Methamphetamine (METH) was reported to caused neurotoxicity and cell death, in vitro. Centella asiatica or ‘pegaga’ is a native tropical herb with antioxidant and neuroprotective activities. Although the effects of Centella asiatica against oxidative stress and neuronal cell death have been reported in previous studies, however, the potential effects of Centella asiatica against psychostimulant methamphetamine (METH) are limited. Therefore, this study was aimed to evaluate the effects of Centella asiatica extract (CAE) against METH on all-trans retinoic acid, RA-differentiated human neuroblastoma, SH-SY5Y cells. The RA-differentiated SH-SY5Y cells were used to resemble dopaminergic neuronal-like cells. Cell viability was quantitatively assessed by 3-(4,5-dimethylthiazol-2-yl)-2 tetrazolium bromide, MTS assay.  CAE at varying concentrations from 1pg/mL to 1mg/mL significantly decreased the viability of the undifferentiated SH-SY5Y cells in a concentration-dependent manner. At 1mg/mL of CAE, significantly increased the viability of differentiated SH-SY5Y cells. Meanwhile, CAE at 100µg/mL and 1mg/mL significantly reversed the METH-induced neuronal cell death. The results revealed that promising treatment of CAE on METH-induced neurotoxicity is mediated by its high content of asiaticoside, asiatic acid, madecassoside and madecassic acid. Taken together, this study may suggest CAE as a potential therapeutic treatment for METH-induced neurotoxicity, in vitro.

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