A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin

// Cynthia Licona 1, * , Marie-Elodie Spaety 1, * , Antonelle Capuozzo 1, 6 , Moussa Ali 4 , Rita Santamaria 6 , Olivier Armant 2 , Francois Delalande 5 , Alain Van Dorsselaer 5 , Sarah Cianferani 5 , John Spencer 3 , Michel Pfeffer 4 , Georg Mellitzer 1 , Christian Gaiddon 1 1 INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Universite de Strasbourg, Section Oncologie FMTS, Strasbourg, France 2 Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), Germany 3 Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, UK 4 Institut of Chemistry, UMR7177 CNRS, Universite de Strasbourg, Laboratory of Metal-Induced Synthesis, France 5 Institut Pluridisciplinaire Hubert Curien, Departement Sciences Analytiques, Universite de Strasbourg, France 6 Department of Pharmacy, University of Naples Federico II, Naples, Italy * These authors contributed equally to this work Correspondence to: Christian Gaiddon, email: gaiddon@unistra.fr Keywords: epigenetics, ruthenium, p53, ER stress, cisplatin Received: September 02, 2016      Accepted: October 17, 2016      Published: November 30, 2016 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.