Molecular pharmacological investigation of archazolid for the intervention with inflammation and cancer
The vacuolar H+ -ATPase (v-ATPase) constitutes a crucial enzyme in regulating cellular pH and maintaining pH homeostasis to ensure essential cellular processes in view of processing, trafficking and degradation. Being involved in such indispensable mechanisms, deregulation of the proton translocating enzyme has been linked to many diseases [1-3], when the tight control of the pH cannot be maintained. The v-ATPase has thus been emphasized as potential drug target. The myxobacterial compound archazolid inhibits the v-ATPase in the low nanomolar range  and has further been evidenced to potently induce apoptotic mechanisms in tumor cells . As promising agent for future anti-cancer therapies it was of particular relevance to investigate whether archazolid also affects primary immune cells that are components of the tumor microenvironment. In this context, macrophages as representative cells of the innate and adaptive immune system were addressed in this work. Thus, several assays with macrophages differentiated from freshly isolated monocytes were performed. The ability of macrophages to polarize upon activating stimuli into the pro-inflammatory but anti-tumoral M1 phenotype and the M2 phenotype with opposing properties  was further addressed in the investigation of archazolid. Especially concerning cancer occurrence the predominating macrophage subtype (i.e. M2) is significant for tumor development and disease progress. This is mainly attributable to a variety of mediators formed by macrophages dependent on their polarization . This thesis comprises two parts which focus on distinct groups of mediators and whether they are affected by archazolid: the first part concerns a selection of tumor-relevant pro- and anti-inflammatory cytokines. The second part approaches the modulation of the arachidonic acid (AA) cascade by archazolid, where in turn both pathways, lipoxygenase (LO) and cyclooxygenase (COX) pathway, were considered.
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