title: A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin.
abstract: Ruthenium complexes are considered as potential replacements for platinum compounds in oncotherapy. Their clinical development is handicapped by a lack of consensus on their mode of action. In this study, we identify three histones (H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium compound (RDC11). Using purified histones, we confirmed an interaction between the ruthenium complex and histones that impacted on histone complex formation. A comparative study of the ruthenium complex versus cisplatin showed differential epigenetic modifications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modifications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures specific for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to specificities distinguishing the ruthenium complex from cisplatin. For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways. To further understand the role of HDACs in these regulations, we used suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin cytotoxicity while antagonizing the ruthenium complex activity. This study provides critical information for the characterization of signaling pathways differentiating both compounds, in particular, by the identification of a non-DNA direct target for an organoruthenium complex.
authors.affiliation: INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Licona
authors.affiliation: INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France.
authors.forename: Marie-Elodie
authors.initials: ME
authors.lastname: Spaety
authors.affiliation: INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France.|Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Antonelle
authors.initials: A
authors.lastname: Capuozzo
authors.affiliation: Institut of Chemistry, UMR7177 CNRS, Université de Strasbourg, Laboratory of Metal-Induced Synthesis, France.
authors.forename: Moussa
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Santamaria
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), Germany.
authors.forename: Olivier
authors.initials: O
authors.lastname: Armant
authors.affiliation: Institut Pluridisciplinaire Hubert Curien, Département Sciences Analytiques, Université de Strasbourg, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Delalande
authors.affiliation: Institut Pluridisciplinaire Hubert Curien, Département Sciences Analytiques, Université de Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.affiliation: Institut Pluridisciplinaire Hubert Curien, Département Sciences Analytiques, Université de Strasbourg, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cianferani
authors.affiliation: Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, UK.
authors.forename: John
authors.initials: J
authors.lastname: Spencer
authors.affiliation: Institut of Chemistry, UMR7177 CNRS, Université de Strasbourg, Laboratory of Metal-Induced Synthesis, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Pfeffer
authors.affiliation: INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France.
authors.forename: Georg
authors.initials: G
authors.lastname: Mellitzer
authors.affiliation: INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Gaiddon
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D006657:Histones; D009942:Organometallic Compounds; D012428:Ruthenium; D002945:Cisplatin
keywords: ER stress; cisplatin; epigenetics; p53; ruthenium