EXTH-68. DUAL METABOLIC REPROGRAMMING BY ONC201/TIC10 AND 2-DEOXYGLUCOSE HAS A STRONG ANTIPROLIFERATIVE EFFECT ON MEDULLOBLASTOMA CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi178-vi179
Author(s):  
Annika Dwucet ◽  
Qiyu Cao ◽  
Maximilian Pruss ◽  
Mike-Andrew Westhoff ◽  
Christian Rainer Wirtz ◽  
...  
Keyword(s):  
Proliferative Activity ◽  
Cell Metabolism ◽  
Additional Treatment ◽  
Metabolic Reprogramming ◽  
Molecular Characteristics ◽  
Cellular Viability ◽  
Independent Manner ◽  
Extracellular Flux ◽  
Glycolysis Inhibitor

Abstract BACKGROUND Medulloblastoma represents one of the most common brain tumors in children. While the understanding of the molecular characteristics of this disease has very much advanced, more efficient and less toxic therapeutics are still in high demand. In this study we examined whether the imipridone ONC201/TIC10 affects the metabolic and proliferative activity of medulloblastoma cells alone and in combination with 2-Deoxyglucose in vitro. METHODS Extracellular flux (agilent seahorse) and Western blot analyses were performed to assess effects on tumor cell metabolism and the expression of proteins of the respiratory chain in established medulloblastoma cells. MTT assays and spheroid assays were performed to examine anti-proliferative effects in a 2-D and 3-D setting. RESULTS Treatment with ONC201/TIC10 has a strong inihibitory effect on the cellular viability of different medulloblastoma cells independent of c-Myc expression. While ONC201/TIC10 decreases the oxidative consumption rates in D458 (c-Myc high) and DAOY (c-Myc low) cells, extracellular acidification rates experienced an increase in D458 and a decrease in DAOY cells. Treatment with ONC201/TIC10 in combination with the glycolysis inhibitor 2-Deoxyglucose synergistically inhibited the cellular viability of medulloblastoma cells and impaired the growth of spheroids. CONCLUSION Overall, ONC201/TIC10 profoundly inhibits the proliferative activity of medulloblastoma cells in a c-Myc-independent manner. Additional treatment with the glycolysis inhibitor 2-Deoxyglucose synergistically enhances the anti-medulloblastoma activity of ONC201/TIC10. This promising approach warrants further investigations.

scholarly journals ONC201/TIC10 Is Empowered by 2-Deoxyglucose and Causes Metabolic Reprogramming in Medulloblastoma Cells in Vitro Independent of C-Myc Expression

2021 ◽  
Vol 9 ◽  
Author(s):  
Annika Dwucet ◽  
Maximilian Pruss ◽  
Qiyu Cao ◽  
Mine Tanriover ◽  
Varun V. Prabhu ◽  
...  
Keyword(s):  
Proliferative Activity ◽  
Drug Testing ◽  
Combined Treatment ◽  
Inhibitory Effect ◽  
Additional Treatment ◽  
Metabolic Reprogramming ◽  
Cellular Viability ◽  
Extracellular Flux ◽  
Glycolysis Inhibitor

The purpose of this study was to examine whether the imipridone ONC201/TIC10 affects the metabolic and proliferative activity of medulloblastoma cells in vitro. Preclinical drug testing including extracellular flux analyses (agilent seahorse), MTT assays and Western blot analyses were performed in high and low c-myc-expressing medulloblastoma cells. Our data show that treatment with the imipridone ONC201/TIC10 leads to a significant inihibitory effect on the cellular viability of different medulloblastoma cells independent of c-myc expression. This effect is enhanced by glucose starvation. While ONC201/TIC10 decreases the oxidative consumption rates in D458 (c-myc high) and DAOY (c-myc low) cells extracellular acidification rates experienced an increase in D458 and a decrease in DAOY cells. Combined treatment with ONC201/TIC10 and the glycolysis inhibitor 2-Deoxyglucose led to a synergistic inhibitory effect on the cellular viability of medulloblastoma cells including spheroid models. In conclusion, our data suggest that ONC201/TIC10 has a profound anti-proliferative activity against medulloblastoma cells independent of c-myc expression. Metabolic targeting of medulloblastoma cells by ONC201/TIC10 can be significantly enhanced by an additional treatment with the glycolysis inhibitor 2-Deoxyglucose. Further investigations are warranted.

scholarly journals Succinate Supplement Elicited “Pseudohypoxia” Condition to Promote Proliferation, Migration, and Osteogenesis of Periodontal Ligament Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Huimin Mao ◽  
Andi Yang ◽  
Yunhe Zhao ◽  
Lang Lei ◽  
Houxuan Li
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Oxidative Phosphorylation ◽  
Periodontal Ligament ◽  
Cell Metabolism ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Periodontal Ligament Cells ◽  
Low Oxygen

Most mesenchymal stem cells reside in a niche of low oxygen tension. Iron-chelating agents such as CoCl2 and deferoxamine have been utilized to mimic hypoxia and promote cell growth. The purpose of the present study was to explore whether a supplement of succinate, a natural metabolite of the tricarboxylic acid (TCA) cycle, can mimic hypoxia condition to promote human periodontal ligament cells (hPDLCs). Culturing hPDLCs in hypoxia condition promoted cell proliferation, migration, and osteogenic differentiation; moreover, hypoxia shifted cell metabolism from oxidative phosphorylation to glycolysis with accumulation of succinate in the cytosol and its release into culture supernatants. The succinate supplement enhanced hPDLC proliferation, migration, and osteogenesis with decreased succinate dehydrogenase (SDH) expression and activity, as well as increased hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), suggesting metabolic reprogramming from oxidative phosphorylation to glycolysis in a normal oxygen condition. The succinate supplement in cell cultures promoted intracellular succinate accumulation while stabilizing hypoxia inducible factor-1α (HIF-1α), leading to a state of pseudohypoxia. Moreover, we demonstrate that hypoxia-induced proliferation was G-protein-coupled receptor 91- (GPR91-) dependent, while exogenous succinate-elicited proliferation involved the GPR91-dependent and GPR91-independent pathway. In conclusion, the succinate supplement altered cell metabolism in hPDLCs, induced a pseudohypoxia condition, and enhanced proliferation, migration, and osteogenesis of mesenchymal stem cells in vitro.

scholarly journals Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension

2015 ◽  
Vol 119 (10) ◽  
pp. 1164-1172 ◽  
Author(s):  
Kurt R. Stenmark ◽  
Rubin M. Tuder ◽  
Karim C. El Kasmi
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Expression Patterns ◽  
Metabolic Reprogramming ◽  
Apoptosis Resistance ◽  
Arginase 1 ◽  
Inflammatory Changes

Pulmonary hypertension (PH) is a complex, multifactorial syndrome that remains poorly understood despite decades of research. PH is characterized by profound pulmonary artery (PA) remodeling that includes significant fibro-proliferative and inflammatory changes of the PA adventitia. In line with the emerging concept that PH shares key features with cancer, recent work centers on the idea that PH results from a multistep process driven by reprogramming of gene-expression patterns that govern changes in cell metabolism, inflammation, and proliferation. Data demonstrate that in addition to PA endothelial cells and smooth muscle cells, adventitial fibroblasts from animals with experimental hypoxic PH and from humans with PH (hereafter, termed PH-Fibs) exhibit proinflammatory activation, increased proliferation, and apoptosis resistance, all in the context of metabolic reprogramming to aerobic glycolysis. PH-Fibs can also recruit, retain, and activate naïve macrophages (Mϕ) toward a proinflammatory/proremodeling phenotype through secretion of chemokines, cytokines, and glycolytic metabolites, among which IL-6 and lactate play key roles. Furthermore, these fibroblast-activated Mϕ (hereafter, termed FAMϕ) exhibit aerobic glycolysis together with high expression of arginase 1, Vegfa, and I1lb, all of which require hypoxia-inducible factor 1α and STAT3 signaling. Strikingly, in situ, the adventitial Mϕ phenotype in the remodeled PA closely resembles the Mϕ phenotype induced by fibroblasts in vitro (FAMϕ), suggesting that FAMϕ crosstalk involving metabolic and inflammatory signals is a critical, pathogenetic component of vascular remodeling. This review discusses metabolic and inflammatory changes in fibroblasts and Mϕ in PH with the goal of raising ideas about new interventions to abrogate remodeling in hypoxic forms of PH.

scholarly journals Potential adverse effects of ciprofloxacin and tetracycline on ARPE-19 cell lines

2020 ◽  
Vol 5 (1) ◽  
pp. e000458
Author(s):  
Nasim Salimiaghdam ◽  
Lata Singh ◽  
Kevin Schneider ◽  
Angele Nalbandian ◽  
Marilyn Chwa ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Cell Lines ◽  
Transforming Growth Factor ◽  
Cell Metabolism ◽  
Retinal Pigment ◽  
Interleukin 1 ◽  
Retinal Pigment Epithelial Cells ◽  
Cellular Viability

BackgroundWe aim to determine the possible adverse effects of ciprofloxacin (CPFX) and tetracycline (TETRA), as examples of bactericidal and bacteriostatic agents, respectively, on cultured human retinal pigment epithelial cells (ARPE-19).MethodsCells were treated with 30, 60 and 120 µg/mL of CPFX and TETRA. Cell metabolism was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. JC-1 dye (5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide) assay was conducted to measure the mitochondrial membrane potential (MMP). The level of reactive oxygen species (ROS) was measured using the -2’,7’-dichlorodihydrofluorescein diacetate assay (H2DCFDA). Quantitative real-time PCR was performed to analyse the gene expression levels associated with apoptosis (BAX, BCL2-L13, BCL2, Caspase 3, Caspase 7 and Caspase 9), inflammatory (interleukin-1β (IL-1β), IL-6, IL-33, transforming growth factor-α (TGF-α), TGF-β1 and TGF-β2) and antioxidant pathways (SOD2, SOD3, GPX3 and NOX4), along with the mitochondrial DNA (mtDNA) copy numbers.ResultsResults illustrated that while all three concentrations of CPFX decreased cellular viability of ARPE-19 during all incubation periods, the 120 µg/mL TETRA resulted in increased cellular viability. At 48 and 72 hours, levels of MMP and ROS decreased significantly with each antibiotic. BAX, BCL2-L13, CASP-7, CASP-9, SOD2 and GPX3 genes overexpressed by either antibiotics. There was higher expression of IL-6 and IL-1B with TETRA treatment. The level of mtDNA decreased using both treatments.ConclusionsClinically relevant concentrations of CPFX and TETRA have detrimental impacts on ARPE-19 cell lines in vitro, including upregulation of genes related to apoptosis, inflammation and antioxidant pathways. Additional studies are warranted to investigate if these harmful effects might be seen in retinal degeneration models in vivo.

Effects of gamma ray on some molecular characteristics of in vitro regenerated Gerbera jamesonii Bolus

1970 ◽  
Vol 39 (2) ◽  
pp. 207-214
Author(s):  
Nazma Akter ◽  
RH Sarker ◽  
MI Hoque
Keyword(s):  
Gamma Ray ◽  
Molecular Characteristics ◽  
Gerbera Jamesonii

DOI: 10.3329/bjb.v39i2.7490Bangladesh J. Bot. 39(2): 207-214, 2010 (December)

(Substituted)-benzo[b]thiophene-4-carboxamide Synthesis and Antiproliferative Activity Study

2020 ◽  
Vol 17 (5) ◽  
pp. 563-573 ◽  
Author(s):  
Chandrakant Dhondiram Pawar ◽  
Dattatraya Navnath Pansare ◽  
Devanand Baburao Shinde
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Proliferative Activity ◽  
Thiophene Ring ◽  
Amide Group ◽  
Peptide Coupling ◽  
Ic50 Value ◽  
Important Building Block ◽  
Mcf 7

Background: Thiophene ring forms important building block in medicinal chemistry. Literature reveals that thiophene ring in combination with different groups shows different activity. By keeping these things in mind we have designed and synthesized a new series of amide and sulfonamide coupled thiophene. A series of novel substituted 3-sulfamoylbenzo[b]thiophene-4- carboxamide molecules containing sulfonamide and amide group were designed, synthesized and used for anti-proliferative activity study. Methods: The final compounds 16-36 were synthesized by using series of reactions comprising sulfonation, sulfonamide coupling, hydrolysis and peptide coupling. The yields of compounds 16- 36 are in the range of 90-98%. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR, 13C NMR, LCMS and the purity was checked through HPLC analysis. The compounds were further tested for their in vitro anticancer activity against a series of cell lines A549, HeLa, MCF-7 and Du-145. Results: The intermediates 8-13, 15 and final compounds 16-36 were synthesized in good yields. The synthesized compounds were further tested for their anticancer activity and most of compounds showed moderate to good anticancer activity against all four cell lines. Conclusion: We have synthesized 21 compounds and were screened for anticancer activity against MCF-7, HeLa, A-549 and Du-145 cancer cell lines. Most of the compounds were active for tested cell lines with IC50 value in the range of 1.81 to 9.73 μM. The compounds 18, 19, 21, 25, 30, 31 and 33 are most active in cell line data with IC50 value in the range of 1.81 to 2.52 μM.

Discovery of N-Phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine Derivatives as Potent Mnk2 Inhibitors: Design, Synthesis, SAR Analysis, and Evaluation of in vitro Anti-leukaemic Activity

2019 ◽  
Vol 15 (6) ◽  
pp. 602-623 ◽  
Author(s):  
Ahmed M. Abdelaziz ◽  
Sarah Diab ◽  
Saiful Islam ◽  
Sunita K.C. Basnet ◽  
Benjamin Noll ◽  
...  
Keyword(s):  
Proliferative Activity ◽  
Myeloid Cell ◽  
Structural Diversity ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cell Leukaemia ◽  
Aberrant Expression ◽  
Design Synthesis ◽  
Induced Apoptosis

Background:Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E) is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity. As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment of cancer.Methods:A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity against MV4-11 AML cells was determined.Results:These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable pharmacokinetic properties and oral bioavailability.Conclusion:This work proposes that exploration of the structural diversity in the context of Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.

scholarly journals NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2999
Author(s):  
Deborah Reynaud ◽  
Roland Abi Nahed ◽  
Nicolas Lemaitre ◽  
Pierre-Adrien Bolze ◽  
Wael Traboulsi ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Major Gene ◽  
Critical Role ◽  
Orthotopic Model ◽  
Independent Manner ◽  
Maternal Immune Response ◽  
The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

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