Polynuclear ruthenium organometallic compounds induce DNA damage in human cells identified by the nucleotide excision repair factor XPC

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.

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

“…Numerous metal-derived compounds, organometallics, are developed to generate severe DNA alterations [306,307]. Some ruthenium-containing compounds such as polynuclear ruthenium induce DNA damage and recruit DNA repair effectors such as XPC (Xeroderma Pigmentosum complementation group C) [308]. Certain organometallics target enzymes involved in DNA topology (Top1) [309].…”

Selective Targeting of Regulated Rhabdomyosarcoma Cells by Trinuclear Ruthenium(II)–Arene Complexes

“…Given that 1 shows potent cytotoxicity and ruthenium­(II) arene complexes are generally known to induce DNA damage leading to cell death, the ability of 1 to induce DNA damage was studied by monitoring the levels of γH2AX, a protein related to the DNA damage pathway. − The levels of γH2AX, a robust marker for DNA double-strand breaks, were markedly increased in a dose-dependent manner in both RMS cell lines (Figure a) indicating that 1 indeed induces DNA damage.…”