Präklinische Evaluation von Organogold-Verbindungen zur Therapie maligner Erkrankungen

Cancer is on the rise worldwide and continues to represent an enormous burden for society as well as the healthcare system. Hardly any other field has developed as much in recent decades, both clinically and in terms of research, as tumor therapy. And although the lethality of many malignant diseases has been significantly reduced, therapy failure still plays an important role. Cytostatic resistance, whether intrinsic or acquired, may be causative in this regard. Decades ago, the cytotoxic potential of platinum was discovered, sparking interest in metal compounds for the treatment of malignant diseases. Platinum-containing derivatives are still used in the majority of current therapeutic regimens. Despite this, a variety of side effects and resistance limit therapeutic options and there is a constant interest in exploring novel compounds, including new metal compounds. To date, however, few are in clinical use. In recent decades, there has been increasing interest in organometallic compounds such as NHC-gold complexes. The cytotoxic mechanism of action has been widely described as binding of thioredoxin reductase, concomitant generation of Reactive Oxygen Species and mitochondrial apoptosis. This cumulative dissertation investigates the cytotoxicity of various organogold complexes (NHC-Au(I) compounds) on different immortalized cancer cell lines and thus whether they represent potential antitumor agents. In this regard, the work includes two publications in the form of initial preclinical studies. The mechanism of action under investigation is apoptosis. The hypothesis that the substances act primarily via the mitochondrial signaling pathway was to be evaluated. The focus here is on the interaction with various proteins of the Bcl-2 family. The analysis of stressors responsible for this, such as the formation of Reactive Oxygen Species and the inhibition of the oxidoreductase thioredoxin reductase, represents a sub-point. A large part of the work involves the comparison of the substances on native starting cells as well as cultured offshoot cells with induced cytostatic resistance. This allows conclusions to be drawn about the potential for overcoming resistance as well as the mode of action when the mechanism of resistance is known. The results of both publications show that the best investigated compounds in the nanomolar range have cytotoxic and cytostatic activity on leukemia and lymphoma cells in vitro. Apoptosis was thereby detected on various immortalized cancer cell lines, but not on cultured healthy human leukemia cells. Thus, a mechanism of action that is dependent on cell division can be assumed. The first publication "Novel gold(I) complexes induce apoptosis in leukemia cells via the ROS-induced mitochondrial pathway with an upregulation of hara-kiri and overcome multi-drug resistances in leukemia and lymphoma cells and sensitize drug-resistant tumor cells to apoptosis in vitro" also elaborates on the involvement of mitochondrial apoptosis. iv Characteristics are the involvement of different Bcl-2 proteins, the breakdown of the mitochondrial transmembrane potential and the efflux of mitochondrial proteins such as cytochromes C and Smac. The involvement of ROS could be indirectly demonstrated here. For the compounds in the publication "Gold(I) Bis(1,2,3-triazol-5-ylidene) Complexes as Promising Selective Anticancer Compounds", inhibition of thioredoxin reductase could only be determined to a moderate extent. Resistance overcomes were observed on a variety of cytostatic-resistant cancer cells in both publications. Exciting results were obtained by comparing a substance of the former publication on some initial cells and cytostatic drug-resistant daughter cells derived therefrom, which developed over- or underexpression of various Bcl-2 proteins in the course of their resistance formation. The organogold complex studied not only showed resistance overcomes on these, but three resistant cell lines were significantly more sensitive to the compound. This supports the notion that Bcl-2 family proteins, as indicators of the mitochondrial apoptosis pathway, are important players in the mechanism of action of this gold complex and suggests that it subverts and collapses the resistance mechanism. In summary, the organogold compounds investigated here show exciting potential for further exploration in the therapy of malignant diseases in the initial preclinical studies.