Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflammatory Drugs [Elektronische Ressource] / Raminder Singh. Gutachter: Ulrich Rüther. Betreuer: Rainer Haas

Rudra

Sujets

• Gesundheit

Informations

• Publié par: heinrich-heine-universitat_dusseldorf
• Publié le: 01 janvier 2011
• Nombre de lectures: 42
• Poids de l'ouvrage: 5 Mo

Extrait

Molecular mechanisms of the anti-
leukemic properties of Non-steroidal Anti
Inflammatory Drugs




Kumulative - Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von
Raminder Singh
2011

Aus der Klinik für Hämatologie, Onkologie und klinische Immunologie der Heinrich-Heine Universität Düsseldorf







Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. med. Rainer Haas Koreferent: Prof. Dr. rer. nat. Ulrich Rüther
thTag der mündlichen Prüfung: 13 October 2011
Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflammatory Drugs


ॐ अ सतो मा सद्गमय ।
तमसो मा यज् ो� तग मयर् ।।
मत् योमार्म तं गमय । ृ ृ
ॐ शा ि त शा ि त शा ि त ।।
– ब हद ा र ण्य क उप� नषद् 1.3.28

Translation
om asato mā sadgamaya
tamaso mā jyotirgamaya
mṛtyor mā amṛtaṁ gamaya
OM śānti śānti śānti
– b ṛ ha dār a ṇyak upani ṣad 1.3.28

Translation
Lead me (by giving knowledge) from the unreal to the real;
From darkness (of ignorance) to the light (of knowledge);
From fear of death (sense of limitation) to the Knowledge immortality (limitless liberation)
OM - Let There Be Peace Peace Peace.
– Brihadaranyaka Upanishad 1.3.28
Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflammatory Drugs
ृ
न् न् न्
Table of Contents I

Table of Contents

ABBREVIATIONS ........................................................................................................................................................... II
ZUSAMMENFASSUNG .................................................................................................................................................. V
ABSTRACT .................................................................................................................................................................. VII
CITATIONS OF PUBLICATIONS IN THIS DISSERTATION ................................................................................................ IX
1. INTRODUCTION ................................................................................................................................................... 1
1.1 PERFECTIVE ASPECT ......................................................................................................................................... 1
1.2 LEUKAEMIA .................................................................................................................................................... 2
1.3 ACUTE MYELOID LEUKAEMIA (AML) ................................................................................................................... 3
1.4 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) ..................................................................................... 4
1.5 EFFECTS OF NSAIDS ON CANCER ................................................................................................ 5
1.6 NSAIDS USED IN PRESENT STUDY .............................................. 6
1.6.1 Sulindac Sulfide ...................................................................................................................................... 6
1.6.2 Diclofenac ............................................................................ 7
1.6.3 OSI-461 .................................................................................................................................................. 7
1.7 CELL-CYCLE ............................................................ 7
1.7.1 Cell-cycle regulation............................................................................................................................... 8
1.7.2 Cell-cycle regulators ............................................. 9
1.7.3 Cell-cycle check points ........................................................................................................................... 9
1.8 CELL CYCLE AND APOPTOSIS ............................................ 11
1.9 APOPTOSIS .................................................................................................................................................. 12
1.9.1 Apoptosis can occur through two pathways ....................................................................................... 13
1.10 JNKS .......................................................................................................................................................... 13
1.11 AP-1 FAMILY.................................................................................................................................... 14
1.11.1 c-Jun .......................................................................................................... 14
1.11.2 JunB .............................................................................................................................. 15
1.11.3 Fra2 ................................................................... 15
1.12 GADDS ................................................................................ 15
1.13 MDA-7/IL-24 ............................................................................................................................................. 16
2. AIM OF THIS STUDY .................................................................................................................. 17
3. PERSONAL BIBLIOGRAPHY ................................................................................................................................ 18
3.1 PUBLICATIONS OF DISSERTATION ...................................................................................................................... 18
3.2 OTHER PUBLICATIONS .................................................................................................................................... 18
4. PUBLICATIONS OF THE DISSERTATION ............................................................................................................. 19
4.1 THE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS SULINDAC SULFIDE AND DICLOFENAC INDUCE APOPTOSIS AND
DIFFERENTIATION IN HUMAN ACUTE MYELOID LEUKEMIA CELLS THROUGH AN AP-1 DEPENDENT PATHWAY. .................................. 20
4.2 THE NOVEL COMPOUND OSI-461 INDUCES APOPTOSIS & GROWTH ARREST IN HUMAN ACUTE MYELOID LEUKEMIA CELLS. . 50
5. SUMMARY AND DISCUSSION ............................................................................................................................ 60
6. REFERENCES ............................................................................................................................... 65
7 ACKNOWLEDGMENT ......................................................................................................................................... 75
8 DECLARATION ................................................................................................................................................... 76
Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflammatory Drugs

Abbreviations II

Abbreviations
AAD 7-Amino-Actinomycin D
% Percentage
°C Degree Celsius
Ab Antibody
ABTS 2,2'-azino-di-(3-athylbenzthiazolin sulfonal)
AML Acute myeloid leukaemia
APS Ammonium Per-sulphate
ATP Adenosine-Tri-Phosphate
BM Bone Marrow
BrdU Bromodeoxyuridine (5-bromo-2'-deoxyuridine)
BSA Bovine Serum Albumin
bp Base pairs
cAMP Cyclic adenosine mono phosphate
CDK Cyclin dependent kinase
CDS Coding Sequence
CFU Colony forming unit
CKI Cyclin dependent kinase inhibitor
CLP Common Lymphoid Progenitor
CML Chronic myeloid leukaemia
Cy5 Cyanine 5 Dye
DMSO Dimethylsulfoxide
DTT Dithiothreitol
E.coli Escherichia coli
ECL Enhanced chemo luminescence
EDTA Ethylenediamine tetraacetic acid
ELISA Enzyme linked immunosorbant assay
Epo Erythropoietin

Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflammatory Drugs
Abbreviations III

e.g. For example (exempli gratia)
EtBr Ethidiumbromide
EtOH Ethanol
ERKs Extracellular signal regulated kinases
FACS Fluorescence Activated Cell Sorting (Flow Cytometry)
FBS Fetal Bovine Serum
FCS Fetal Calf Serum
FITC Fluoresceine Isothiocyanate
FSC Forward Scatter
G-CSF Colony stimulating factor 3 (granulocyte)
GM-CSF Granulocyte-Macrophage Colony-Stimulating-Factor
HSC Haematopoietic Stem Cell
IL Interleukin
IP Immunprecipitation
JNK c-Jun N-terminal kinase
kB Kilo base
kDa Kilo Dalton
L-Glu L-Glutamine
LB Luria broth
MAPK Mitogen-activated protein kinase
MEP Myeloid-Erytheroid Progenitors
mg Milligram
MNCs Mononuclear cells
MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-
MTS
tetrazolium)
NP-40 Nonidet P-40
NSAIDs Non-steroidal Anti Inflammatory Drugs
N-terminal Amino terminal
OD Optical Density
Molecular mechanisms of the anti-leukemic properties of Non-steroidal Anti Inflamma