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

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posted on 2023-06-09, 04:37 authored by Cynthia Licona, Marie-Elodie Spaety, Antonella Capuozzo, Moussa Ali, Rita Santamaria, Olivier Armant, Francois Delalande, Alain Van Dorsselaer, Sarah Cianferani, John SpencerJohn Spencer, Michel Pfeffer, Georg Mellitzer, Christian Gaiddon
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Oncotarget

ISSN

1949-2553

Publisher

Impact Journals

Issue

2

Volume

8

Page range

2568-2584

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-01-11

First Open Access (FOA) Date

2017-01-11

First Compliant Deposit (FCD) Date

2017-01-11

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