A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium( ii ) metallo-intercalator

Substitutionally inert ruthenium( ii ) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen) 2 (tpphz)] 2+ (phen = 1,10-phenanthroline, tpphz = tet...

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Published in:Chemical science (Cambridge) Vol. 9; no. 4; pp. 841 - 849
Main Authors: Gill, Martin R., Jarman, Paul J., Halder, Swagata, Walker, Michael G., Saeed, Hiwa K., Thomas, Jim A., Smythe, Carl, Ramadan, Kristijan, Vallis, Katherine A.
Format: Journal Article
Language:English
Published: England Royal Society of Chemistry 2018
Subjects:
Cancer
Chemistry
Damage
Deoxyribonucleic acid
DNA
DNA damage
Metallography
Reagents
Replication
Ruthenium
Ruthenium compounds
Stalling
ISSN:2041-6520, 2041-6539
Online Access:Get full text
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Summary:Substitutionally inert ruthenium( ii ) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen) 2 (tpphz)] 2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53-deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest. Moreover, mitotic progression is compromised by [Ru(phen) 2 (tpphz)] 2+ , where the generation of metaphase chromosome spindle attachment failure results in spindle assembly checkpoint (SAC) activation. This dual mechanism of action results in preferential growth inhibition of rapidly-proliferating oesophageal cancer cells with elevated mitotic indices. In addition to these single-agent effects, [Ru(phen) 2 (tpphz)] 2+ functions as a radiosensitizer with efficiency comparable to cisplatin, which occurs through a synergistic enhancement of DNA damage. These results establish that DNA replication is the target for [Ru(phen) 2 (tpphz)] 2+ and provide the first experimental evidence that ruthenium-based intercalation targets multiple genome integrity pathways in cancer cells, thereby achieving enhanced selectivity compared to existing DNA-damaging agents such as cisplatin.
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ISSN:2041-6520
2041-6539
DOI:10.1039/C7SC03712K