期刊
ONCOTARGET
卷 8, 期 2, 页码 2568-2584出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13711
关键词
epigenetics; ruthenium; p53; ER stress; cisplatin
资金
- Centre National pour la Recherche Scientifique (CNRS, France)
- ARC
- Ligue contre le Cancer
- AFM
- European action [COST CM1105, COST BM1307]
- SMSdrug.net
- Laboratory of Excellence (LABEX) Chemistry of Complex Systems (UdS)
- FRC (UdS) through the project synergie
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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