Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity

Zenita Adhireksan, Gabriela E. Davey, Pablo Campomanes, Michael Groessl, Catherine M. Clavel, Haojie Yu, Alexey A. Nazarov, Charmian Hui Fang Yeo, Wee Han Ang, Peter Dröge, Ursula Rothlisberger, Paul J. Dyson and Curt A. Davey ()
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Zenita Adhireksan: School of Biological Sciences, Nanyang Technological University
Gabriela E. Davey: School of Biological Sciences, Nanyang Technological University
Pablo Campomanes: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Michael Groessl: Institute of Analytical Chemistry, University of Vienna
Catherine M. Clavel: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Haojie Yu: School of Biological Sciences, Nanyang Technological University
Alexey A. Nazarov: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Charmian Hui Fang Yeo: National University of Singapore
Wee Han Ang: National University of Singapore
Peter Dröge: School of Biological Sciences, Nanyang Technological University
Ursula Rothlisberger: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Paul J. Dyson: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Curt A. Davey: School of Biological Sciences, Nanyang Technological University

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.

Date: 2014
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DOI: 10.1038/ncomms4462

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