scholarly journals The effect of desferrioxamine on transferrin receptors, the cell cycle and growth rates of human leukaemic cells

1986 ◽  
Vol 236 (1) ◽  
pp. 243-249 ◽  
Author(s):  
A Bomford ◽  
J Isaac ◽  
S Roberts ◽  
A Edwards ◽  
S Young ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rates ◽  
Iron Chelator ◽  
Scatchard Analysis ◽  
Transferrin Receptors ◽  
Dependent Inhibition ◽  
Leukaemic Cells ◽  
Dose Dependent Inhibition ◽  
And Control ◽  
Initial Binding

The effect of the iron chelator, desferrioxamine, on transferrin binding, growth rates and the cell cycle was investigated in the human leukaemic cell line, K562. At all concentrations of the chelator (2-50 microM) binding of 125I-transferrin was increased by 24 h and reached a maximum at 72-96 h. Maximum binding (6-8-fold increased) occurred in cells treated with 20 microM-desferrioxamine, in contrast with control cells which, at 96 h, showed a 50% decrease over initial binding. Scatchard analysis at 4 degrees C showed that this increased binding was due to an increase in the number of receptors, as the Kd was similar in induced (1.8 nM) and control (1.5 nM) cells. After 96 h cells, cultured with 20 and 50 microM-desferrioxamine accumulated 59Fe from bovine transferrin at over twice the rate found with control cells, reflecting the increase in transferrin receptors. Although iron uptake was unimpaired by the chelator there was a dose-dependent inhibition of cell growth, with control cells completing three divisions in 96 h and those in 10 microM-desferrioxamine only two divisions. At the highest concentration (50 microM), cell division was abrogated although cell viability was maintained (85%). In contrast, DNA synthesis was not markedly affected, except at 50 microM-desferrioxamine when incorporation of [3H]thymidine was 52% of that in control cells. Flow cytometry revealed that there was a progressive accumulation of the cells in the active phases of their cycle (S, G2 + M). Desferrioxamine may increase transferrin receptors in two ways: by chelating a regulatory pool of iron within the cell, and by arresting cells in S phase when receptors are maximally expressed.

A Novel 4-anilino-3-quinolinecarbonitrile Dual Src and Abl Kinase Inhibitor (SKI-606) Has In Vitro Activity on CML Ph+Blast Cells Resistant to Imatinib.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1991-1991 ◽  
Author(s):  
Tiziana Grafone ◽  
Manuela Mancini ◽  
Emanuela Ottaviani ◽  
Matteo Renzulli ◽  
Frank Boschelli ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
G1 Phase ◽  
Inhibition Of Proliferation ◽  
Cd34 Cells ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Abstract The tyrosine kinase Bcr-Abl is the fusion product of a reciprocal translocation between chromosomes 9 and 22, known as Philadelphia chromosome and it is present in the leukemic cells of more than 95% of patients with chronic myeloid leukemia (CML). Overexpression of Bcr-Abl in myeloid cells activates various signaling pathways. Previous studies have demonstrated that certain Src family kinases, such as Hck and Lyn, are also targets of Bcr-Abl activity. Hck and Lyn are expressed and activated in CML blast-crisis patients and their increased expression correlates with disease progression or STI571 resistance in some CML patients. Resistance to STI571 seems to be mediated by amplification of or mutations in the Bcr-Abl gene, reducing sensitivity to this inhibitor; newer Abl inhibitors may be susceptible to the same mechanism of resistance. Alternative strategies for control of CML, including the biological relevance of the Bcr-Abl - Src family kinase pathway, are necessary. One such strategy is the use of a specific small molecule Src kinase inhibitor. Recently, a new class of compounds, 4-anilino-3-quinolinecarbonitrile Src kinase inhibitors, has been synthesized. One member of this class, SKI606, is a dual-specificity inhibitor of both Src family and Abl kinases. To investigate the effect in vitro of SKI-606, we analyzed human cell lines from CML patients in blast crisis (K562, MK2, LAMA) and CD34+ from 9 patients in CML blast crisis using a wide range of concentrations (0.01μM-10μM) of this novel agent. Cell cycle analysis, in particular for the cell lines, showed that a major effect of SKI606 is to alter cell cycle progression, producing G1/S arrest. SKI606 induced dose-dependent inhibition of proliferation with IC50 of 1μM at 24hr. Flow cytometric analysis with Annexin-V showed that SKI-606 induced apoptosis of 50% of cells at 48hr. Western blotting and immuno-blotting analyses showed reduced phosphorylation of Bcr-Abl and also of Lyn and Hck. We also demonstrated activation of Caspase-9, an effector cysteine-protease, after exposure to SKI606. These drug effects also reduced the oncogenic effects of the Bcr-Abl gene product in CD34+ cells from patients with CML blast crisis. SKI606 induced a dose-dependent inhibition of proliferation with an IC50 of 1μM at 48hr and induction of apoptosis at 72hr. Cytofluorimetric analysis after 72hr of exposure revealed marked accumulation of cells in the G1 phase of cell cycle, accompanied by a significant increase in the number of apoptotic cells. In some of these patient samples, we observed hypophosphorylation of Bcr-Abl, Hck and Lyn at low concentration of SKI606 (1uM at 24h, 10uM at 48h). Interestingly, CD34+ cells taken from two of our imatinib-resistant patients with Bcr-Abl point mutations (E255K and Y253H) in the P-loop region of the protein exhibited a significant increase of apoptosis (50%) and a block in G1 phase of the cell cycle after treatment with 1 μM SKI606 for 48h. Our study thus showed a potential therapeutic usefulness of the drug in treatment of CML, particularly in blast crisis phase. Ongoing gene expression profiles will contribute to further understanding of the drug mechanism.

scholarly journals CXCL9 and CXCL11 Chemokines Modulation by Peroxisome Proliferator-Activated Receptor-α Agonists Secretion in Graves’ and Normal Thyrocytes

2010 ◽  
Vol 31 (5) ◽  
pp. 780-780
Author(s):  
Alessandro Antonelli ◽  
Silvia Martina Ferrari ◽  
Silvia Frascerra ◽  
Cinzia Pupilli ◽  
Caterina Mancusi ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Rt Pcr ◽  
Thyroid Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dependent Inhibition ◽  
Pparγ Agonists ◽  
Dose Dependent Inhibition ◽  
And Control ◽  
Dose Dependent

ABSTRACT Context Peroxisome proliferator-activated receptor (PPAR)-α has been shown to exert immunomodulatory effects in autoimmune disorders. However, until now, no data were present in the literature about the effect of PPARα activation on CXCL9 and CXCL11 chemokines in general or on secretion of these chemokines in thyroid cells. Objective and Design The presence of PPARα and PPARγ has been evaluated by RT-PCR in Graves’ disease (GD) and control cells in primary culture. Furthermore, we have tested the role of PPARα and PPARγ activation on CXCL9 and CXCL11 secretion in GD and control cells after stimulation of these chemokines secretion with IFNγ and TNFα. Results This study shows the presence of PPARα and PPARγ in GD and control cells. A potent dose-dependent inhibition by PPARα-agonists was observed on the cytokines-stimulated secretion of CXCL9 and CXCL11 in GD and control cells. The potency of the PPARα agonists used was maximum on the secretion of CXCL9, reaching about 90% of inhibition by fenofibrate and 85% by ciprofibrate. The relative potency of the compounds was different with each chemokine; for example, gemfibrozil exerted a 55% inhibition on CXCL11, whereas it had a weaker activity on CXCL9 (40% inhibition). PPARα agonists were stronger (ANOVA, P < 0.001) inhibitors of CXCL9 and CXCL11 secretion in thyrocytes than PPARγ agonists. Conclusions Our study shows the presence of PPARα in GD and control thyrocytes. PPARα activators are potent inhibitors of the secretion of CXCL9 and CXCL11, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

scholarly journals CXCL9 and CXCL11 Chemokines Modulation by Peroxisome Proliferator-Activated Receptor-α Agonists Secretion in Graves’ and Normal Thyrocytes

2010 ◽  
Vol 95 (12) ◽  
pp. E413-E420 ◽  
Author(s):  
Alessandro Antonelli ◽  
Silvia Martina Ferrari ◽  
Silvia Frascerra ◽  
Cinzia Pupilli ◽  
Caterina Mancusi ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Thyroid Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dependent Inhibition ◽  
Pparγ Agonists ◽  
Dose Dependent Inhibition ◽  
And Control ◽  
Dose Dependent ◽  
Stimulation Of

Context: Peroxisome proliferator-activated receptor (PPAR)-α has been shown to exert immunomodulatory effects in autoimmune disorders. However, until now, no data were present in the literature about the effect of PPARα activation on CXCL9 and CXCL11 chemokines in general or on secretion of these chemokines in thyroid cells. Objective and Design: The presence of PPARα and PPARγ has been evaluated by real-time-PCR in Graves’ disease (GD) and control cells in primary culture. Furthermore, we have tested the role of PPARα and PPARγ activation on CXCL9 and CXCL11 secretion in GD and control cells after stimulation of these chemokines secretion with IFNγ and TNFα. Results: This study shows the presence of PPARα and PPARγ in GD and control cells. A potent dose-dependent inhibition by PPARα-agonists was observed on the cytokines-stimulated secretion of CXCL9 and CXCL11 in GD and control cells. The potency of the PPARα agonists used was maximum on the secretion of CXCL9, reaching about 90% of inhibition by fenofibrate and 85% by ciprofibrate. The relative potency of the compounds was different with each chemokine; for example, gemfibrozil exerted a 55% inhibition on CXCL11, whereas it had a weaker activity on CXCL9 (40% inhibition). PPARα agonists were stronger (ANOVA, P < 0.001) inhibitors of CXCL9 and CXCL11 secretion in thyrocytes than PPARγ agonists. Conclusions: Our study shows the presence of PPARα in GD and control thyrocytes. PPARα activators are potent inhibitors of the secretion of CXCL9 and CXCL11, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

Differences between antigenic determinants of pig and cat zona pellucida proteins

Reproduction ◽  
2000 ◽  
pp. 15-23 ◽  
Author(s):  
K Jewgenow ◽  
M Rohleder ◽  
I Wegner
Keyword(s):  
In Vitro Fertilization ◽  
Zona Pellucida ◽  
Antigenic Determinants ◽  
Vitro Fertilization ◽  
Contraceptive Vaccine ◽  
Sperm Binding ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Despite many efforts, the control of reproduction in feral cat populations is still a problem in urban regions around the world. Immunocontraception is a promising approach; thus the present study examined the suitability of the widely used pig zona pellucida proteins (pZP) for contraception in feral domestic cats. Purified zona pellucida proteins obtained from pig and cat ovaries were used to produce highly specific antisera in rabbits. Antibodies against pZP raised in rabbits or lions were not effective inhibitors of either in vitro sperm binding (cat spermatozoa to cat oocytes) or in vitro fertilization in cats, whereas antibodies against feline zona pellucida proteins (fZP) raised in rabbits showed a dose-dependent inhibition of in vitro fertilization. Immunoelectrophoresis, ELISA and immunohistology of ovaries confirmed these results, showing crossreactivity of anti-fZP sera to fZP and to a lesser extent to pZP, but no interaction of anti-pZP sera with fZP. It is concluded that cat and pig zonae pellucidae express a very small number of shared antigenic determinants, making the use of pZP vaccine in cats questionable. A contraceptive vaccine based on feline zona pellucida determinants will be a better choice for the control of reproduction in feral cats if immunogenity can be achieved.

Antioxidant effects and in vitro cytotoxicity on human cancer cell lines of flavonoid-rich Flamboyant (Delonix regia (Bojer) Raf.) flower extract

2020 ◽  
Vol 21 ◽  
Author(s):  
Putthiporn Khongkaew ◽  
Phanphen Wattanaarsakit ◽  
Konstantinos I. Papadopoulos ◽  
Watcharaphong Chaemsawang
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Flower Extract ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Murine Leukemia Cell ◽  
Dose Dependent

Background: Cancer is a noncommunicable disease with increasing incidence and mortality rates both worldwide and in Thailand. Its apparent lack of effective treatments is posing challenging public health issues. Introduction: Encouraging research results indicating probable anti-cancer properties of the Delonix regia flower extract (DRE) have prompted us to evaluate the feasibility of developing a type of product for future cancer prevention or treatment. Methods and Results: In the present report, using High Performance Liquid Chromatography (HPLC), we demonstrate in the DRE, the presence of high concentrations of three identifiable flavonoids, namely rutin 4.15±0.30 % w/w, isoquercitrin 3.04±0.02 %w/w, and myricetin 2.61±0.01 % w/w respectively while the IC50 of DPPH and ABTS assay antioxidation activity was 66.88±6.30 µg/ml and 53.65±7.24 µg/ml respectively. Discussion: Our cancer cell line studies using the MTT assay demonstrated DREs potent and dose dependent inhibition of murine leukemia cell line (P-388: 35.28±4.07% of cell viability remaining), as well as of human breast adenocarcinoma (MCF-7), human cervical carcinoma (HeLa), human oral cavity carcinoma (KB), and human colon carcinoma (HT-29) cell lines in that order of magnitude. Conclusion: Three identifiable flavonoids (rutin, isoquercitrin and myricetin) with high antioxidation activity and potent and dose dependent inhibition of murine leukemia cell line and five other cancer cell lines were documented in the DRE. The extract’s lack of cytotoxicity in 3 normal cell lines is a rare advantage not usually seen in current antineoplastic agents. Yet another challenge of the DRE was its low dissolution rate and long-term storage stability, issues to be resolved before a future product can be formulated.

Investigation on the antibacterial activity of electronic cigarette liquids (ECLs): a proof of concept study

2020 ◽  
Vol 21 ◽  
Author(s):  
Virginia Fuochi ◽  
Massimo Caruso ◽  
Rosalia Emma ◽  
Aldo Stivala ◽  
Riccardo Polosa ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Bacterial Species ◽  
A549 Cells ◽  
Bactericidal Effect ◽  
Minimal Bactericidal Concentration ◽  
Viability Assay ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Background: The key ingredients of e-cigarettes liquid are commonly propane-1,2-diol (also called propylene glycol) and propane-1,2,3-triol (vegetal glycerol) and their antimicrobial effects are already established. The nicotine and flavors which are often present in e-liquids can interfere with the growth of some microorganisms. Objective: The effect of the combining these elements in e-liquids is unknown. The aim of the study was to investigate the possible effects of these liquids on bacterial growth in the presence or absence of nicotine and flavors. Methods: Susceptibilities of pathogenic strains (Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis and Sarcina lutea) were studied by means of a multidisciplinary approach. Cell viability and antioxidant assays were also evaluated. Results: All e-liquids investigated showed antibacterial activity against at least one pathogenic strain. A higher activity was correlated to the presence of flavors and nicotine. Discussion: In most cases the value of minimal bactericidal concentration is equal to the value of minimal inhibitory concentration showing that these substances have a bactericidal effect. This effect was observed in concentrations up to 6.25% v/v. Antioxidant activity was also correlated to presence of flavors. Over time, the viability assay in human epithelial lung A549 cells showed a dose-dependent inhibition of cell growth. Conclusion: Our results have shown that flavors considerably enhance the antibacterial activity of propane-1,2-diol and propane-1,2,3-triol. This study provides important evidence that should be taken into consideration in further investigative approaches, to clarify the different sensitivity of the various bacterial species to e-liquids, including the respiratory microbiota, to highlight the possible role of flavors and nicotine.

scholarly journals In VitroActivities of Hexaazatrinaphthylenes against Leishmania spp.

2015 ◽  
Vol 59 (5) ◽  
pp. 2867-2874 ◽  
Author(s):  
Atteneri López-Arencibia ◽  
Daniel García-Velázquez ◽  
Carmen M. Martín-Navarro ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Content Type ◽  
Inhibition Effect ◽  
Intracellular Amastigotes ◽  
Dependent Inhibition ◽  
Leishmania Spp ◽  
Dose Dependent Inhibition ◽  
Dose Dependent ◽  
Potential Use

ABSTRACTThein vitroactivity of a novel group of compounds, hexaazatrinaphthylene derivatives, against two species ofLeishmaniais described in this study. These compounds showed a significant dose-dependent inhibition effect on the proliferation of the parasites, with 50% inhibitory concentrations (IC50s) ranging from 1.23 to 25.05 μM against the promastigote stage and 0.5 to 0.7 μM against intracellular amastigotes. Also, a cytotoxicity assay was carried out to in order to evaluate the possible toxic effects of these compounds. Moreover, different assays were performed to determine the type of cell death induced after incubation with these compounds. The obtained results highlight the potential use of hexaazatrinaphthylene derivatives againstLeishmaniaspecies, and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.

μ-Opiate Receptors in Neuronal Primary Cultures from Cerebral Cortex

1990 ◽  
Vol 17 (3) ◽  
pp. 177-181
Author(s):  
Peter S. Eriksson ◽  
Elisabeth Hansson ◽  
Lars Rönnbäck
Keyword(s):  
Cerebral Cortex ◽  
Primary Cultures ◽  
Opiate Receptors ◽  
Neuronal Cultures ◽  
Camp Accumulation ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Neuronal Primary Cultures ◽  
Dose Dependent ◽  
Μ Receptor

The presence of μ-opioid receptors was demonstrated as effects of receptor stimulation on PGE1-induced cAMP accumulation in neuronal-enriched primary cultures from rat cerebral cortex. Morphine was used as a μ-receptor agonist. There was a dose-dependent inhibition of the PGE1-stimulated cAMP accumulation by morphine, blocked by the μ-receptor antagonist naloxone. These findings suggest that these neuronal cultures express μ-receptors, possibly connected to adenylate cyclase via an inhibitory Gi-protein. The probable use of functional μ-receptors in neurotoxicological tests is discussed.

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