Abstract
Ruthenium organometallic compounds represent an attractive avenue in developing alternatives to platinum-based chemotherapeutic agents. While evidence has been presented indicating ruthenium-based compounds interact with isolated DNA in vitro, it is unclear what effect these compounds exert in cells. Moreover, the antibiotic efficacy of polynuclear ruthenium organometallic compounds remains uncertain. In the present study, we report that exposure to polynuclear ruthenium organometallic compounds induces recruitment of damaged DNA sensing protein Xeroderma pigmentosum Group C into chromatin-immobilized foci. Additionally, we observed one of the tested polynuclear ruthenium organometallic compounds displayed increased cytotoxicity against human cells deficient in nucleotide excision repair (NER). Taken together, these results suggest that polynuclear ruthenium organometallic compounds induce DNA damage in cells, and that cellular resistance to these compounds may be influenced by the NER DNA repair phenotype of the cells.
Highlights
Ruthenium compounds are an attractive and actively researched alternative to platinum-based chemotherapeutics
Only ∼10% of DMSO treated nuclei contain three or more Xeroderma pigmentosum complementation group C protein (XPC) foci. These results suggest that nuclei with less than three XPC foci represent the baseline DNA damage load due to endogenous genotoxins and exposure to the DMSO solvent
Replicate experiments support the observed trend that exposure to the ruthenium compounds results in an average of a five-fold increase in the percentage of nuclei with three or more XPC foci. These results suggest that exposure to the polynuclear ruthenium compounds induce DNA damage in cells that is identified by the XPC DNA damage sensor protein
Summary
Ruthenium compounds are an attractive and actively researched alternative to platinum-based chemotherapeutics. As part of a study, looking at the development of ruthenium cage molecules based on a 2,4,6-tris(di-2-pyridylamino)-1,3,5-triazine ligand system (Figure 1), we reported on the synthesis of star-shaped trinuclear complexes [13] These polynuclear ruthenium organometallic compounds were shown to interact with DNA in vitro, and are effective in binding to human proteins [14]. We had hypothesized that in a mechanism similar to what is usually proposed for mononuclear compounds, the Ru-chloride bond would hydrolyze in vitro to provide a reactive intermediate with a Ru-H2O bond [15,16,17] This intermediate would covalently bind to DNA molecules generating single-stranded adducts. These properties suggest the potential of polynuclear ruthenium organometallic compounds to form bulky covalent DNA lesions. These compounds displayed underwhelming cytotoxic effects when evaluated against a triple-negative breast cancer cell line [13]
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