Interactions of Metal-based Anticancer Drugs in Cancer Cells

Thanks to the advances in modern medicine, deaths attributable to communicable diseases such as infections are steadily decreasing. On the contrary, more people die of noncommunicable diseases every year - it is expected that by the year 2030, noncommunicable conditions will account for approximately 70% of all deaths worldwide with cancer being the single most contributing factor. Over the last decades, considerable efforts have been made to understand the mode of action of platinum-based anticancer agents, especially cisplatin, which shows excellent activities against certain cancer types such as testicular carcinoma but which lacks activity against other tumor types with high mortality rates (e.g. lung and colon carcinoma). It has been shown that binding towards DNA takes place put there is still skepticism if this represents the only contributing factor towards anticancer activity. As an alternative to platinum-based drugs, organometallic compounds incorporating ruthenium as the central atom have received increased attention in the medicinal coordination chemistry community as their mode of action is supposed to differ significantly compared to the platinum complexes. Clinical trials have been completed for two ruthenium compounds, showing promising results such as a broad spectrum of activity and low toxicity. In order to further increase the efficiency of the drug development process, identification of the chemotherapeutics` targets on a cellular level is of critical importance. An in-depth characterization of the binding towards biomolecules such as proteins and DNA might shed new light on the differences between platinum- and ruthenium-based anticancer agents in terms of anticancer-action and identification of the ultimate targets will provide guidance for the rational design of novel drugs. The proposed project deals with an exhaustive analysis of the distribution of metal-based drugs in different cell compartments as well as their exact quantification. For qualitative characterization of proteinaceous targets as well as covalent modifications of DNA, subcellular fractionation of human cancer cells treated with the chemotherapeutics followed by enzymatic digestion and (multidimensional) liquid chromatography - high resolution mass spectrometry will be carried out, whereas inductively coupled plasma - mass spectrometry will be employed for quantitation. By comparison of results for sensitive and resistant cell lines, further insight into the detoxification and resistance mechanisms as well as the causes for undesired side-effects will be gained which will in turn help in the efficient synthesis of novel chemotherapeutics and in the design of innovative treatment strategies.