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

Licona, Cynthia, Spaety, Marie-Elodie, Capuozzo, Antonella, Ali, Moussa, Santamaria, Rita, Armant, Olivier, Delalande, Francois, Van Dorsselaer, Alain, Cianferani, Sarah, Spencer, John, Pfeffer, Michel, Mellitzer, Georg and Gaiddon, Christian (2017) A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin. Oncotarget, 8 (2). pp. 2568-2584. ISSN 1949-2553

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0146 Inorganic chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: John Spencer
Date Deposited: 11 Jan 2017 10:48
Last Modified: 06 Mar 2017 09:14
URI: http://sro.sussex.ac.uk/id/eprint/66108

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