Einfluss nichtsteroidaler Antirheumatika (NSAR) auf die Proteinexpression von Neuroblastomzellen

In vielen epidemiologischen und Placebo-kontrollierten randomisierten Studien, in unterschiedlichsten Tier- und Zell-Modellen wurde bereits die Tumorgenese-hemmende und Apoptose-induzierende Wirkung der Wirkstoffklasse der NSAR belegt. Dabei wurden und werden verschiedene Mechanismen, die im Zusamme...

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Bibliographic Details
Main Author: Fründ, Detlef
Contributors: Kuschinsky, Klaus (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2006
Online Access:PDF Full Text
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Table of Contents: A lot of epidemiological and placebo-controlled randomised studies and a set of very different animal- and cell-models have already supported the tumourgenesis inhibitory and apoptosis inducing effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In this context various mechanisms of inhibition of proliferation and induction of apoptosis are discussed. Within the scope of the present work the described effects of the NSAIDs at the example of the non-selective Cox-1/Cox-2-inhibitor flufenamic acid was examined in a neuroblastoma cell line and was confirmed. Thus relatively unspecific experiments like MTT-assays and analyses of the cellmorphology have verified the inhibitory effect of flufenamic acid regarding the viability, activity and proliferation of the cells of the neuroblastoma cell line KELLY. More specific investigations like apoptosis-assays with acridineorange and ethidiumbromide (AO/EB-staining) and FACS-analyses with propidiumiodide have shown that under the influence of flufenamic acid in adequate concentrations the neuroblastoma cells induce apoptosis. For the proteome analyses a concentration of 500 µM flufenamic acid was chosen. In this concentration clear effects were to be observed at the described experiments. Besides, this concentration clearly lay about the concentration necessary for the inhibition of the cyclooxygenases basing on the presumption that the effect is also to be led back on cyclooxygenase independent mechanisms which respond only to higher concentrations. Thus with proteome analyses of the neuroblastoma cells which were treated more than 3 h, 6 h, 9 h and 12 h with 500 µM flufenamic acid twelve proteins were differently regulated compared to the control group. A connection of these proteins with the inhibition of the cyclooxygenases has been unknown up to now. Only three, namely Hsp75, Hsc70/54 and Lbp, are mentioned directly or indirectly related to NSAIDs. The group of these identified proteins must be called rather heterogeneous. Thus the three proteins Hsp75, Hsc70/54 and TCP-1ε are known to be molecular chaperones. Four other proteins, Eno-1, PK-M1/M2, PDC-E2 and MDH1, are directly or indirectly involved in the production and supply of energy by means of glycolysis. RbP0, eEF2 and sEF2b are regulating enzymes of the translation. And p47 is involved as a co-factor of p97 in fusion of membranes, whereas Lbp act as a laminin receptor. In spite of the partly very different functions most of these with flufenamic acid regulated proteins were already mentioned regarding apoptosis, cell proliferation and cancer. A connection between the described observations at the cellular level, the known effects of NSAIDs on apoptosis and proliferation and the identified regulated proteins at molecular level is obvious. On the one hand the results of this work offer new starting points for further investigations of the mechanisms by which NSAIDs induce apoptosis and inhibit proliferation. On the other hand some of the regulated proteins could be pharmacological targets for the therapy of cancer.