scholarly journals Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Donna L. Nile ◽  
Colin Rae ◽  
David J. Walker ◽  
Joe Canning Waddington ◽  
Isabel Vincent ◽  
...  
Keyword(s):  
High Risk ◽  
Apoptotic Cell ◽  
Cell Metabolism ◽  
Neuroblastoma Cells ◽  
Glioma Cells ◽  
High Risk Disease ◽  
Rigorous Treatment ◽  
Atp Generation ◽  
Inhibition Of Glycolysis ◽  
Cancer Cell Metabolism

Abstract Background Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. Methods Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. Results The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. Conclusion Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by its combination with metformin. This clearly demonstrates that dual metabolic targeting has potential to improve clinical outcomes in children with high-risk neuroblastoma by overcoming radioresistance.

scholarly journals Temporal Quantitative Proteomics Analysis of Neuroblastoma Cells Treated with Bovine Milk-Derived Extracellular Vesicles Highlights the Anti-Proliferative Properties of Milk-Derived Extracellular Vesicles

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 750
Author(s):  
Pamali Fonseka ◽  
Taeyoung Kang ◽  
Sing Chee ◽  
Sai V. Chitti ◽  
Rahul Sanwlani ◽  
...  
Keyword(s):  
High Risk ◽  
Extracellular Vesicles ◽  
Quantitative Proteomics ◽  
Cell Metabolism ◽  
Bovine Milk ◽  
Neuroblastoma Cells ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Label Free ◽  
The Impact

Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the treatment strategies have improved in the recent years, the survival rate of high-risk NBL patients remain poor. Hence, it is crucial to explore new therapeutic avenues to sensitise NBL. Recently, bovine milk-derived extracellular vesicles (MEVs) have been proposed to contain anti-cancer properties. However, the impact of MEVs on NBL cells is not understood. In this study, we characterised MEVs using Western blotting, NTA and TEM. Importantly, treatment of NBL cells with MEVs decreased the proliferation and increased the sensitivity of NBL cells to doxorubicin. Temporal label-free quantitative proteomics of NBL cells highlighted the depletion of proteins involved in cell metabolism, cell growth and Wnt signalling upon treatment with MEVs. Furthermore, proteins implicated in cellular senescence and apoptosis were enriched in NBL cells treated with MEVs. For the first time, this study highlights the temporal proteomic profile that occurs in cancer cells upon MEVs treatment.

Treatment of breast, ovarian and lung cancer cells by inducing apoptosis with a deep eutectic solvent prepared from 2-deoxy-D-glucose and metformin: Cancer cell metabolism as a drug target.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15599-e15599
Author(s):  
Sauli Vuoti ◽  
Jaakko Eemil ◽  
Kumar Narasimha ◽  
Kai Reinikainen
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Apoptotic Cell ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Deep Eutectic Solvent ◽  
Migration And Invasion ◽  
Solvent Mixtures ◽  
Human Beings ◽  
Cancer Cell Metabolism

e15599 Background: Targeting cancer cell metabolism has gained attention as a future strategy to fight cancer. A characteristic of tumor cells is the elevated aerobic glycolysis for energy production. It has been shown that 2-deoxy-D-glucose (2DG) inhibits glycolysis and induces apoptotic cell death in different tumor types. The anti-diabetic drug metformin has been used in combination to enhance the inhibitory effect. So far, the attempts to combine both compounds in a clinical setting have been limited by the requirement of concentrations higher than those accessible in blood plasma of human beings. Deep eutectic solvents (DES) are solvent mixtures prepared from hydrogen bond donors and acceptors, wherein pharmaceutically active compounds can also be one of the components. Besides having unique physicochemical properties, DESs have been reported to demonstrate or enhance anticancer properties. Methods: We developed a DES mixture from 2DG and MET using a method based in mechanical grinding. We investigated the anticancer activity of conventional and DES mixtures of MET and 2DG, and used the mixtures to inhibit the growth, migration and invasion of cancer cells, and induce cell cycle arrest in vitro. Results: MET and 2DG, alone and in combination, induced apoptosis in the H460, SKOV-3, MDA-MB-231 and HCC1806 (TNBC) cell lines. Induction of apoptosis was further quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. DES mixtures had the highest impact on cell viability, exceeding the effect of 2DG/MET as single agents or combinations at all clinically relevant concentrations. The DES mixture with the lowest concentration to induce apoptosis consisted of 100 µM 2DG and 200 µM MET. A conventional solution with similar concentrations showed no activity. Conclusions: We developed a DES from 2DG/MET, which significantly reduced the viability of several types of cancer cells, surpassing the effect of single components or mixtures. The DES does not necessitate the use of additional solvents and could be used to develop clinical applications for targeting cancer cell metabolism.

scholarly journals Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 396
Author(s):  
Timon A. Bloedjes ◽  
Guus de Wilde ◽  
Jeroen E. J. Guikema
Keyword(s):  
Multiple Myeloma ◽  
Cell Metabolism ◽  
Chromosomal Rearrangements ◽  
Chromosomal Translocations ◽  
Metabolic Effects ◽  
Aberrant Expression ◽  
Metabolic Functions ◽  
Complex Chromosomal Rearrangements ◽  
Cancer Cell Metabolism ◽  
The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

scholarly journals A Holistic Evolutionary and 3D Pharmacophore Modelling Study Provides Insights into the Metabolism, Function, and Substrate Selectivity of the Human Monocarboxylate Transporter 4 (hMCT4)

2021 ◽  
Vol 22 (6) ◽  
pp. 2918
Author(s):  
Eleni Papakonstantinou ◽  
Dimitrios Vlachakis ◽  
Trias Thireou ◽  
Panayiotis G. Vlachoyiannopoulos ◽  
Elias Eliopoulos
Keyword(s):  
Cancer Cell ◽  
Structural Characteristics ◽  
Cell Metabolism ◽  
Intracellular Localization ◽  
Selective Inhibition ◽  
Monocarboxylate Transporter ◽  
Cancer Drug ◽  
Pharmacophore Modelling ◽  
Anti Cancer ◽  
Cancer Cell Metabolism

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.

scholarly journals Inhibition of Glycolysis Suppresses Cell Proliferation and Tumor Progression In Vivo: Perspectives for Chronotherapy

2021 ◽  
Vol 22 (9) ◽  
pp. 4390
Author(s):  
Jana Horváthová ◽  
Roman Moravčík ◽  
Miroslava Matúšková ◽  
Vladimír Šišovský ◽  
Andrej Boháč ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Progression ◽  
Umbilical Vein ◽  
Cell Metabolism ◽  
High Rate ◽  
Ki 67 ◽  
Immunodeficient Mice ◽  
Inhibition Of Glycolysis

A high rate of glycolysis is considered a hallmark of tumor progression and is caused by overexpression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Therefore, we analyzed the possibility of inhibiting tumor and endothelial cell metabolism through the inhibition of PFKFB3 by a small molecule, (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15), as a promising therapy. The effects of PFK15 on cell proliferation and apoptosis were analyzed on human umbilical vein endothelial cells (HUVEC) and the human colorectal adenocarcinoma cell line DLD1 through cytotoxicity and proliferation assays, flow cytometry, and western blotting. The results showed that PFK15 inhibited the proliferation of both cell types and induced apoptosis with decreasing the Bcl-2/Bax ratio. On the basis of the results obtained from in vitro experiments, we performed a study on immunodeficient mice implanted with DLD1 cells. We found a reduced tumor mass after morning PFK15 treatment but not after evening treatment, suggesting circadian control of underlying processes. The reduction in tumor size was related to decreased expression of Ki-67, a marker of cell proliferation. We conclude that inhibition of glycolysis can represent a promising therapeutic strategy for cancer treatment and its efficiency is circadian dependent.

scholarly journals Clinical Presentation and Management of a Dinutuximab Beta Extravasation in a Patient with Neuroblastoma

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 91
Author(s):  
Michael Launspach ◽  
Marita Seif ◽  
Theresa M. Thole ◽  
Patrick Jesse ◽  
Joachim Schulz ◽  
...  
Keyword(s):  
High Risk ◽  
Neuroblastoma Cells ◽  
Drug Application ◽  
Immunocompromised Host ◽  
Laboratory Diagnostics ◽  
Chemotherapy Drugs ◽  
Reactive Protein ◽  
Intravenous Antibiotics ◽  
Inflammatory Toxicity ◽  
Bacterial Superinfection

Extravasation can present serious accidental complication of intravenous drug application. While monoclonal antibodies do not show the necrotic potential of cytotoxic chemotherapy drugs, considerable inflammatory toxicity can occur, necessitating standardized operating procedures for the management of their extravasation. Here, we report the clinical course and management of dinutuximab beta extravasation in a 3-year-old child. Dinutuximab beta is a chimeric monoclonal antibody targeting the GD2 disialoganglioside on the surface of neuroblastoma cells that has in recent years gained significant importance in the treatment of high-risk neuroblastoma, now contributing to both first- and second-line therapy protocols. The dinutuximab beta extravasation reported here occurred when the patient received the antibody cycle as a continuous infusion over a 10-day period after haploidentical stem cell transplantation for relapsed high-risk neuroblastoma. The extravasated dinutuximab beta caused local pain, swelling, and hyperemia accompanied by fever and an overall deterioration in the general condition. Laboratory diagnostics demonstrated an increase in C-reactive protein level and total white blood cell count. Clinical complication management consisted of intravenous fluid therapy, local dabbing with dimethyl sulfoxide (DMSO), analgesia with dipyrone, as well as application of intravenous antibiotics to prevent bacterial superinfection in the severely immunocompromised host. The patient considerably improved after six days with this treatment regimen and fully recovered by day 20.

scholarly journals Oncolytic Virotherapy: The Cancer Cell Side

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 939
Author(s):  
Marcelo Ehrlich ◽  
Eran Bacharach
Keyword(s):  
Viral Replication ◽  
Cancer Cell ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Oncolytic Viruses ◽  
Oncogenic Signaling ◽  
Functional Connection ◽  
Immunity Genes ◽  
Cancer Cell Metabolism ◽  
Editing Process

Cell autonomous immunity genes mediate the multiple stages of anti-viral defenses, including recognition of invading pathogens, inhibition of viral replication, reprogramming of cellular metabolism, programmed-cell-death, paracrine induction of antiviral state, and activation of immunostimulatory inflammation. In tumor development and/or immunotherapy settings, selective pressure applied by the immune system results in tumor immunoediting, a reduction in the immunostimulatory potential of the cancer cell. This editing process comprises the reduced expression and/or function of cell autonomous immunity genes, allowing for immune-evasion of the tumor while concomitantly attenuating anti-viral defenses. Combined with the oncogene-enhanced anabolic nature of cancer-cell metabolism, this attenuation of antiviral defenses contributes to viral replication and to the selectivity of oncolytic viruses (OVs) towards malignant cells. Here, we review the manners by which oncogene-mediated transformation and tumor immunoediting combine to alter the intracellular milieu of tumor cells, for the benefit of OV replication. We also explore the functional connection between oncogenic signaling and epigenetic silencing, and the way by which restriction of such silencing results in immune activation. Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.

scholarly journals Using routinely collected primary care records to identify and investigate severe asthma: a scoping review

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Jonathan Stewart ◽  
Frank Kee ◽  
Nigel Hart
Keyword(s):  
Primary Care ◽  
High Risk ◽  
Severe Asthma ◽  
Scoping Review ◽  
Asthma Severity ◽  
Data Sources ◽  
Full Potential ◽  
High Risk Disease ◽  
Asthma Outcomes ◽  
Disease Variant

AbstractShielding during the coronavirus pandemic has highlighted the potential of routinely collected primary care records to identify patients with ‘high-risk’ conditions, including severe asthma. We aimed to determine how previous studies have used primary care records to identify and investigate severe asthma and whether linkage to other data sources is required to fully investigate this ‘high-risk’ disease variant. A scoping review was conducted based on the Arksey and O’Malley framework. Twelve studies met all criteria for inclusion. We identified variation in how studies defined the background asthma cohort, asthma severity, control and clinical outcomes. Certain asthma outcomes could only be investigated through linkage to secondary care records. The ability of primary care records to represent the entire known asthma population is unique. However, a number of challenges need to be overcome if their full potential to accurately identify and investigate severe asthma is to be realised.

scholarly journals Indirubin exerts anticancer effects on human glioma cells by inducing apoptosis and autophagy

AMB Express ◽  
2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhaohui Li ◽  
Han Wang ◽  
Jun Wei ◽  
Liang Han ◽  
Zhigang Guo
Keyword(s):  
Apoptotic Cell ◽  
Treatment Strategies ◽  
Glioma Cells ◽  
Annexin V ◽  
Metastatic Potential ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Efficient Treatment ◽  
Cell Percentage ◽  
Anticancer Effects

Abstract Glioma causes significant mortality across the world and the most aggressive type of brain cancer. The incidence of glioma is believed to increase in the next few decades and hence more efficient treatment strategies need to be developed for management of glioma. Herein, we examined the anticancer effects of Indirubin against a panel of human glioma cells and attempted to explore the underlying mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay showed that Indirubin could inhibit the growth of all the glioma cells but the lowest IC50 of 12.5 µM was observed against the U87 and U118 glioma cells. Additionally, the cytotoxic effects of Indirubin were comparatively negligible against the normal astrocytes with an IC50 of > 100 µM. Investigation of mechanism of action, revealed that Indirubin exerts growth inhibitory effects on the U87 and U118 glioma cells by autophagic and apoptotic cell death. Annexin V/PI staining assay showed that apoptotic cell percentage increased dose dependently. Apoptosis was associated with increase in Bax decrease in Bcl-2 expressions. Additionally, the expression of autophagic proteins such as LC3II, ATG12, ATG15 and Beclin 1 was also increased. Wound heal assay showed that Indirubin caused remarkable decrease in the migration of the U87 and U118 cells indicative of anti-metastatic potential of Indirubin. Taken together, these results suggest that Indirubin exerts potent anticancer effects on glioma cells and may prove essential in the management of glioma.

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