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The Effect of Environmental Stress and Selective Glucocorticoid Receptor Modulators on Chicken and Human Leukaemia Cells

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The Effect of Environmental Stress and Selective Glucocorticoid Receptor Modulators on Chicken and Human Leukaemia Cells The Effect of Environmental Stress and Selective Glucocorticoid Receptor Modulators on Chicken and Human Leukaemia Cells Israa Najm Abdullah Al-Ibadi A thesis submitted to the University Of Salford in partial fulfilment of the requirements for the degree of Doctor of Philosophy in School of Environment & Life Sciences, College of Science & Technology, 2017 Word Count: 56, 135 Table of Contents 1 Introduction and aims…………………………………………………………………………………………………….25 1.1 Introduction......................................................................................................... 25 1.1.1 Cancer…………………………………………………………………………………………………….25 1.1.1.1 Cancer definition, prevalence and causes ............................................ 25 1.1.1.2 Hallmarks of cancer .............................................................................. 33 1.1.1.3 Cancer therapy ..................................................................................... 36 1.1.1.4 Blood Cancer ......................................................................................... 38 1.1.2 Leukaemia………………………………………………………………………………………………43 1.1.2.1 Acute lymphoblastic leukaemia (ALL), symptoms, causes and treatment …………………………………………………………………………………………………………44 1.1.2.2 Avian lymphoid leukosis…………………………………………………………………..48 1.1.3 Glucocorticoid hormones…….…………………………...............................................49 1.1.3.1 Hypothalamic-pituitary-adrenal axis .. ………………………………………………50 1.1.3.2 GCs uses in medicine ................................................................................ 52 1.1.3.3 Glucocorticoid receptor (GR) ................................................................ 57 1.1.3.3.1 GR domain organisation ..................................................................... 58 1.1.3.3.2 Transcriptional regulation by GR ........................................................ 60 1.1.3.3.3 Levels of control of the GR function................................................... 61 1.1.3.3.4 GR cofactors ....................................................................................... 66 1.1.3.3.5 GR post-translational modifications ................................................... 67 1.1.3.3.6 GR phosphorylation ............................................................................ 69 1.1.4 Cell death………………………………………………………………………………………………..73 1.1.4.1 GR role in control of apoptosis…………………………………………………………79 1.1.5 Selective glucocorticoid receptor modulators or agonists:………………………82 1.1.5.1 Overview of SGRM/SGRA ..................................................................... 82 1.1.5.1.1 Examples of SGRM ............................................................................. 83 1.1.5.1.2 Compound A ....................................................................................... 87 1.1.5.1.3 Overview of non-steroidal compounds used in the study……………..94 2 1.2 Aims of project……………………………………………………………………………………………..96 2 Materials and Methods……………………………………………………………..……………….…………98 2.1 Materials………………………………………………………………………………………………………………… ……98 2.1.1 Tissue culture reagents…………………………………………………………………………..98 2.1.2 Tested compounds, antibodies and kits used in the experiments………….99 2.2 Methods…………………………………………………………………………………………………… ….100 2.2.1 Cancer cell lines…………………………………………………………………………………….100 2.2.1.1 Maintenance of the cells .................................................................... 101 2.2.1.2 Passaging of the cells .......................................................................... 102 2.2.1.3 Counting of the cells ........................................................................... 103 2.2.1.4 Freezing of the cells ............................................................................ 103 2.2.1.5 Thawing of cells………………………………………………………………………………104 2.2.2 Compounds used in the study……………………………………………………………….104 2.2.3 Proliferation assay (MTS or MTT) to measure cytotoxic effect of the drugs 105 2.2.4 Flow cytometry……………………………………………………………………………………..106 2.2.4.1 Cell cycle progression analysis -Propidium Iodide staining ................ 106 2.2.4.2 Apoptosis assay - Annexin V-FitC labelling ......................................... 107 2.2.4.3 ROS measurement- DCFDA staining to measure intracellular ROS ... 109 2.2.5 Immunoblotting assay……………………………………………………………………………110 2.2.5.1 Cellular extract preparation and determination of protein concentration ........................................................................................................ 110 2.2.5.2 Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS PAGE) and Western blotting ................................................................................. 112 2.2.5.3 Western blot solutions and buffers ....................................................... 113 2.2.6 Quantification of relative gene expression…………………………………………….116 Human primers ..................................................................................................... 116 2.2.6.1 Purification of Total RNA from the cells ............................................. 117 2.2.6.2 qRT-PCR…………………………………………………………………………………………….…120 2.2.7 Detection of nitric oxide by Griess reagent…………………………………………122 2.2.8 IL-6 and IL-2 detection by ELISA assay……………………………………………………124 3 2.2.9 Caspase assay………………………………………………………………………………………..127 2.2.10 Ligand-protein binding in-silico simulation- Chimera docking……………………128 2.2.10 Drug stability determination…………………………………………………………………128 3 Results………………………………………………………………………………………………..............................130 3.1 Identification and preliminary characterization of novel compounds……….….130 3.2 Ligand-protein binding- in silico assay……………………………………………………..….132 3.3 Cytotoxicity of DEX and tested compounds………………………………………..……..…137 3.3.1 Cytotoxicity of tested compounds upon 72h incubation with 10µM to 100µM concentrations……………………………………………………………………………………….137 3.3.2 Cytotoxicity of tested compounds upon 48h incubation with 10µM to 100µM concentrations…………………………………………………………………………………………140 3.3.3 Cytotoxicity of tested compounds upon variable duration of treatment and 0 to 2.5 µM concentrations………………………………………………………………………….…….142 3.3.3.1 Cytotoxicity profiles of CEM-C7-14 cells……………………………….………142 3.3.3.2 Cytotoxicity profiles of CEM-C1-15 cells………………………………..……….144 3.3.3.3 Cytotoxicity profiles of DT40 cells………………………………………………..145 3.3.3.4 Cytotoxicity of CPDB and C…………………………………………………….……..146 3.3.3.5 Cytotoxicity of tested compounds on peripheral blood mononuclear cells ……………………………………………………………………………………………………..148 3.3.4 Effect of temperature stress on drug response in ALL and PBMCs…………150 3.3.5 Compound cytotoxicity in cancer and non-cancer epithelial cells………….154 3.4 Flow cytometric analysis of cellular effects of studied compounds ........... ……156 3.4.1 Effects of tested compounds on cell cycle progression………………………….156 3.4.1.1 Effect of tested compounds on CEM-C7-14 cell cycle distribution .... 156 3.4.1.2 Effect of tested compounds on CEM-C1-15 cell cycle distribution .... 158 3.4.1.3 Effect of tested compounds on DT40 cell cycle distribution .............. 159 3.4.1.4 Effect of tested compounds on cell cycle distribution of PBMCs....... 161 3.4.2 Induction of apoptosis of the leukaemia cells treated with studied compounds………………………………………………………………………………………………………….162 3.4.3 Effect of studied compounds on reactive oxygen species (ROS) levels…..165 4 3.5 Caspase-8- enzyme modulation by tested compounds ............................ ……..170 3.6 Human and chicken proteins similarity ............................................................. 171 3.7 Gene and protein expression analysis .............................................................. 172 3.7.1 Analysis of gene expression and protein levels in CEM-C7-14 cells………..173 3.7.2 Analysis of gene expression and protein levels in CEM-C1-15 cells………..177 3.7.3 Analysis of gene expression and protein levels in DT40 cells………………….180 3.8 Regulation of inflammatory mediators by steroid hormone andthe tested compounds ................................................................................................................... 183 3.8.1 Griess Nitric oxide test…………………………………………………………………………..183 3.8.2 Secreted Interleukine 6 modulation……………………………………………………..186 3.8.3 Secreted Interleukine 2 modulation……………………………………………………..188 3.8.4 Regulation of interleukin genes by activated GR upon tested compounds ……………………………………………………………………………………………………………………..190 4 Discussion, conclusions and future work…………………………………………………………………..193 4.1.1 Cytotoxic effects of studied compounds………………………………………………..193 4.1.2 Effects of studied compounds on inflammatory process……………………….202 4.1.3 Molecular analysis of investigated agents interactions…….......................205 4.2 Conclusions........................................................................................................ 208 4.3 Future work ....................................................................................................... 211 4.4 References ......................................................................................................... 214 4.5 Supplementary material .................................................................................... 247 4.5.1 NMR Spectra…………………………………………………………………………………………247 4.5.1.1 Dexamethasone .................................................................................. 247 4.5.1.2 Compound A ......................................................................................
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