Research Papers:

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

Cynthia Licona, Marie-Elodie Spaety, Antonelle Capuozzo, Moussa Ali, Rita Santamaria, Olivier Armant, Francois Delalande, Alain Van Dorsselaer, Sarah Cianferani, John Spencer, Michel Pfeffer, Georg Mellitzer and Christian Gaiddon _

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Oncotarget. 2017; 8:2568-2584. https://doi.org/10.18632/oncotarget.13711

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Cynthia Licona1,*, Marie-Elodie Spaety1,*, Antonelle Capuozzo1,6, Moussa Ali4, Rita Santamaria6, Olivier Armant2, Francois Delalande5, Alain Van Dorsselaer5, Sarah Cianferani5, John Spencer3, Michel Pfeffer4, Georg Mellitzer1, Christian Gaiddon1

1INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France

2 Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), Germany

3Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, UK

4Institut of Chemistry, UMR7177 CNRS, Université de Strasbourg, Laboratory of Metal-Induced Synthesis, France

5Institut Pluridisciplinaire Hubert Curien, Département Sciences Analytiques, Université de Strasbourg, France

6Department of Pharmacy, University of Naples Federico II, Naples, Italy

*These authors contributed equally to this work

Correspondence to:

Christian Gaiddon, email: [email protected]

Keywords: epigenetics, ruthenium, p53, ER stress, cisplatin

Received: September 02, 2016     Accepted: October 17, 2016     Published: November 30, 2016


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.

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