Protein targets for anticancer metal based drugs

Owing to the extensive investigations carried out on cisplatin soon after its discovery, anticancer metal-based drugs- as a category - were believed to target nuclear DNA selectively and cause cancer cell death primarily through a direct DNA damage, according to the so called “DNA paradigm.” In contrast to this concept, it is now widely accepted that proteins, beyond nucleic acids, play an essential role in the mode of action of anticancer metal drugs. Notably, for certain classes of metal-based drugs, e.g. the cytotoxic gold and ruthenium compounds, proteins rather than nucleic acids are the nearly exclusive targets, an opposite situation with respect to the DNA paradigm. Investigating proteins as targets for anticancer metallodrugs and elucidating the associated protein metalation processes is not trivial owing to the intrinsic high complexity of the biological systems and of the cellular proteomes. However, thanks to a research strategy recently developed in our laboratory, mostly grounded on the combined use of electrospray ionization mass spectrometry (ESI MS) and X-ray crystallography, it is possible to characterize in the atomic detail the metalation of a variety of individual proteins. A few instructive examples of metallodrug-protein adducts analyzed according to this strategy are herein provided. Protein metalation may result into protein's loss of function triggering a cascade of cellular processes eventually leading to cancer cell death. Yet, describing in detail protein metalation taking place within the real cellular environment where thousands of proteins -instead of a single one- are simultaneously present, remains a very ambitious and challenging goal for researchers. The emerging omics technologies are starting to shed some light on these issues; a few relevant examples featuring the smart implementation of innovative Chemical Proteomics and Metalloproteomics approaches in the search of the true targets for metallodrugs are herein presented. The perspectives for future work in the area are delineated.