title: Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity.
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 [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-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.
authors.affiliation: 1] Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore [2].
authors.forename: Zenita
authors.initials: Z
authors.lastname: Adhireksan
authors.affiliation: 1] Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore [2].
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Davey
authors.affiliation: 1] Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland [2] Computational Biophysics, German Research School for Simulation Sciences, D-52425 Jülich, Germany [3].
authors.forename: Pablo
authors.initials: P
authors.lastname: Campomanes
authors.affiliation: Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Groessl
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Clavel
authors.affiliation: Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Haojie
authors.initials: H
authors.lastname: Yu
authors.affiliation: 1] Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland [2].
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Nazarov
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
authors.forename: Charmian Hui Fang
authors.initials: CH
authors.lastname: Yeo
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.affiliation: Division of Molecular Genetics and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Peter
authors.initials: P
authors.lastname: Dröge
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rothlisberger
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Curt A
authors.initials: CA
authors.lastname: Davey
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D000081007:Cymenes; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D012428:Ruthenium / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000081007:Cymenes; D008024:Ligands; D039821:Monoterpenes; D011506:Proteins; C007210:4-cymene; D012428:Ruthenium; D004247:DNA