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Carnosine's Inhibitory Effect on Glioblastoma Cell Growth Is Independent of Its Cleavage

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Carnosine's Inhibitory Effect on Glioblastoma Cell Growth Is Independent of Its Cleavage Carnosine’s inhibitory effect on glioblastoma cell growth is independent of its cleavage Dissertation zur Erlangung des akademischen Grades Dr. med. an der Medizinischen Fakultät der Universität Leipzig eingereicht von: Katharina Purcz Geburtsdatum / Geburtsort: 26.05.1988/Leipzig angefertigt an der: Universität Leipzig Klinik und Poliklinik für Neurochirurgie Betreuer: Prof. Dr. Frank Gaunitz Prof. Dr. Jürgen Meixensberger Beschluss über die Verleihung des Doktorgrads vom: 23.02.2021 1 Inhaltsverzeichnis 1. List of Abbreviations ...................................................................................................................... 3 2. Introduction.................................................................................................................................... 5 2.1. Glioblastoma ........................................................................................................................... 5 Risk factors ..................................................................................................................................... 5 Localization and histopathology of glioblastoma ........................................................................ 5 Molecular pathology ............................................................................................................................ 6 Clinic................................................................................................................................................ 6 Prognosis and treatment ............................................................................................................... 6 2.2. Carnosine ................................................................................................................................ 7 Occurrence ...................................................................................................................................... 7 Enzymes and transporters ............................................................................................................ 7 Functions ........................................................................................................................................ 9 Carnosine and cancer ..................................................................................................................... 9 Carnosine and its possible application for therapy ................................................................... 10 2.3. Histidine and other histidine-containing compounds ......................................................... 11 L-histidine and naturally occurring dipeptides.......................................................................... 11 Physiological functions of L-histidine ......................................................................................... 11 L-histidine in health and disease ................................................................................................. 12 L-histidine as a precursor of other metabolites ......................................................................... 12 2.4. Objectives of the study ......................................................................................................... 14 3. Publication .................................................................................................................................... 15 3.1. General informations ........................................................................................................... 15 3.2. Carnosine’s inhibitory effect on glioblastoma cell growth is independent of its cleavage 16 3.3. Supplemental materials ....................................................................................................... 29 4. Summary ............................................................................................................................................ 35 5. References .......................................................................................................................................... 39 6. Appendix ....................................................................................................................................... 47 6.1. Declaration of independent work ....................................................................................... 47 6.2. Statement of the own contribution ..................................................................................... 48 6.3. Curriculum vitae ................................................................................................................... 49 6.4. List of publications ............................................................................................................... 50 6.5. Acknowledgements .............................................................................................................. 51 2 1. List of Abbreviations AGEs Advanced glycation end products AICAR 5-aminoimidazole-4-carboxamide ribonucleotide ALEs Advanced lipoxidation end products ATP Adenosine triphosphate BCAN Brevican BMI Body Mass Index CBTRUS Central Brain Tumor Registry of the United States CD Cluster of Differentiation CN Carnosinase CNS Central Nervous System CO Carbon monoxide COX-2 Cyclooxygenase 2 CS Carnosine Synthase DLL3 Delta like 3 protein DNA Desoxyribonucleic acid EC Enzyme Commission EGFR Epidermal Growth Factor Receptor EORTC Organization for Research and Treatment of Cancer FGFR Fibroblast Growth Factor Receptor GBM Glioblastoma multiforme GSH Glutathione HCD Histidine containing dipeptides His Histidine HRG Histidine-rich glycoprotein IDH Isocitrate dehydrogenase MET N-methyl-N′-nitroso-guanidine human osteosarcoma transforming gene MG Methylglyoxal MGMT O6-methylguanine DNA methyltransferase mRNA messenger RNA mTORC1 Mechanistic target of rapamycin complex 1 NCIC National Cancer Institute of Canada NF1 Neurofibromin 1 NO Nitric oxide OS Overall Survival PCNA Proliferating cell antigen PDGFRA Platelet Derived Growth Factor Receptor Alpha PEPT Oligopeptide transporter 3 PFS Progression-free survival pH Potentia hydrogenii PHT Peptide/histidine transporter PI3 Phosphatidylinositol 3 PI3K Phosphoinositide-3-kinase POT Proton-coupled oligopeptide transporter PRPP 5-phosphoribosyl-1-pyrophosphate PTEN Phosphatase and Tensin homolog qPCR Quantitative Real Time Polymerase Chain Reaction RNA Ribonucleic acid RNS Reactive nitrogen species ROS Reactive oxygen species RT Radiotherapy RTK Receptor tyrosine kinase RT-qPCR Reverse Transcription qPCR STAT3 Signal transducer and activator of transcription 3 TMZ Temozolomide TTF Tumor treating fields VEGF Vascular endothelial growth factor WHO World Health Organization YKL40 also known as Chitinase-3-like protein 1 (CHI3L1) 4 2. Introduction 2.1. Glioblastoma Appearing with a large clinical and histopathological heterogeneity, glioblastoma (GBM) represents the most common and malignant brain tumor. The WHO classifies glioblastoma as a grade IV tumor, which is estimated to occur with an annual incidence of 3.20 per 100 000 population in the US. With a percentage of 55.4% it takes up the majority of primary and other CNS gliomas [98]. This oncologic disease is most common at a median age of 64 at the moment of diagnosis and has its highest incidence in patients aged 65 years and older [84, 98]. In addition, its occurrence rate is almost 1.57-times higher among men than women, and it appears 1.93-times more frequently in Whites than in Afro-Americans [98]. Risk factors There is a huge list of factors, suspected of causing malignant brain tumors: vinyl chloride, pesticides, smoking, petroleum refining, synthetic rubber manufacturing, as well as electromagnetic fields, formaldehyde or nonionizing radiation from cell phones [27]. However, none of the previous clinical trials could ensure significant risk factors [87]. Solely evidence for ionizing radiation has been confirmed to cause GBM tumor development. Furthermore, hereditary diseases such as neurofibromatosis 1 and 2, tuberous sclerosis, Li-Fraumeni syndrome, retinoblastoma or Turcot syndrome are linked to a higher risk of developing high and low grade brain tumors [27], but only 5% of glioma patients exhibit a positive familial anamnesis [87]. Localization and histopathology of glioblastoma With a frequency of 61%, primary gliomas appear in one of the four brain lobes: 25% frontal lobe, 20% temporal lobe, 13% parietal lobe and 3% occipital lobe [27]. Uncommon in the spinal cord and cerebellum, glioblastomas often emerge in the brainstem of children, known as malignant brainstem tumor glioma. Spreading through the corpus callosum and arising with symmetric and bilateral extension, the "butterfly glioma" depicts an often observed manifestation [66]. Whereas apoptotic cell demise is rare, the most distinctive feature of glioblastoma is the occurrence of necrosis (~80% of the total tumor mass) caused by increased tumor cell proliferation resulting in insufficient perfusion. Hypoxia on the other hand causes an intensive excrescence of blood vessels, allowing aggressive growth and promotion of tumor invasivity. By contrast, vascular penetration and consequently hematogenous dissemination, as well as extraneural metastasis, remain rare [66]. Histopathologically, a pronounced mitotic activity in slightly differentiated cells completes the pleomorphic cellular structure [66]. Moreover, small, but also possibly giant cells, partially hyperchromatic nuclei with atypia generate the microscopic image of the WHO IV
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