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Title: The effect of environmental stress and selective glucocorticoid receptor modulators on chicken and human leukaemia cells
Author: Al-Ibadi, I. N. A.
ISNI:       0000 0004 6500 1418
Awarding Body: University of Salford
Current Institution: University of Salford
Date of Award: 2017
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Glucocorticoids (GCs) play important functions in human physiology, and are commonly prescribed anti-inflammatory and immunosuppressive drugs. GCs are used in treatment of childhood acute lymphocytic leukemia (ALL), however resistance to therapy and side effects highlight the need for further research. Glucocorticoids exert their function through binding to intracellular protein glucocorticoid receptor (GR). It is believed that the desired apoptotic effect on cancer cells and anti-inflammatory properties of GCs are due to the GR’s mediated trans-repression function, and that genes positively regulated by GR may mediate unwanted GCs effects. Thus, this study aimed to investigate compounds that would potentially dissociate transcriptional activation from repression, minimize the side effects and GC resistance, towards improving childhood leukemia therapy. The recently developed selective GR modulator (SGRM) Compound A (CPDA) and synthetic GC dexamethasone (DEX) were used together with two “single ring” organic compounds; Tyramine (T) and Tyramine hydrochloride (THCl), as well as Compound B and Compound C, to assess their cytotoxic and anti-inflammatory effects. Molecular modelling has indicated that these compounds contact several residues similar to classical GCs. DEX, CPDA, T and THCL all show cytotoxic effect on GC sensitive and GC resistant ALL CEM-C7-14 and CEM-C1-15 cell lines respectively, as well as chicken derived leukemia cells DT40. Compound B and C showed growth stimulatory effects and were not studied further. Leukaemia cells proliferation was mostly inhibited by high doses and long incubation time, whereas combination of compound treatment with either high or low temperature interfered with this effect. All compounds had marginal growth inhibitory effect on proliferation of normal lung bronchial cells Beas-2b and MCF-C7, whereas T and THCL showed some stimulatory effect on HACAT cells proliferation. Compounds exerted selective and differential effects on cell cycle progression, apoptosis and caspase-8 enzyme activation. Normal peripheral blood mononuclear cells (PBMCs) were used to examine the cytotoxic effect on normal leukocytes. PBMCs were not significantly affected suggesting that tested compounds don’t have the growth suppressive effect on normal peripheral white blood cells. Cell type specific, anti-inflammatory action of studied compounds was measured by ROS, nitrite and cytokine production analysis. Evaluation of secretory cytokines IL-6 and IL-2 by ELISA has shown a cell specific regulation of these biomarkers of inflammation. Protein and gene expression of GR target genes and resistance markers was regulated in a drug and cell dependent manner. These data provided evidence of CPDA, T and THCL capability to inhibit leukemia cells proliferation and alter selected GR target genes expression. Thereby, these compounds show promising characteristics for drug development aiming to potential use in treatment of leukemia and inflammatory conditions.
Supervisor: Not available Sponsor: Iraqi Ministry of Higher Education and Scientific Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available