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Article Dans Une Revue Oncotarget Année : 2017

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

Armant Olivier

Résumé

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 puriied histones, we conirmed 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 modiications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modiications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures speciic for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to speciicities 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 identiication of a non-DNA direct target for an organoruthenium complex.

Domaines

Chimie

Dates et versions

hal-01483834 , version 1 (06-03-2017)

Identifiants

Citer

Licona Cynthia, Spaety Marie-Elodie, Capuozzo Antonella, Ali Moussa, Santamaria Rita, et al.. A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin. Oncotarget, 2017, 8 (2), pp.2568-2584. ⟨10.18632/oncotarget.13711⟩. ⟨hal-01483834⟩
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