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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways
Cynthia Licona1, Marie-Elodie Spaety1, Antonelle Capuozzo1,2
1INSERM 1113, Molecular Signaling of the Cell Stress Response and Pathology, Université de Strasbourg, Section Oncologie FMTS, Strasbourg, France.
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.
Insights
This study identifies histones as targets for a novel ruthenium complex anticancer drug, revealing distinct epigenetic and signaling pathway impacts compared to cisplatin. This offers new insights into organoruthenium compound mechanisms.
Area of Science:
- Oncology
- Medicinal Chemistry
- Epigenetics
Background:
- Ruthenium complexes show promise as platinum alternatives in cancer therapy.
- Understanding their mechanism of action is crucial for clinical development.
Purpose of the Study:
- To identify targets of an anticancer redox organoruthenium compound (RDC11).
- To compare the mode of action of RDC11 with cisplatin, focusing on epigenetic modifications and signaling pathways.
Main Methods:
- Interaction studies with purified histones (H3.1, H2A, H2B).
- Comparative analysis of RDC11 and cisplatin effects on histone modifications and gene expression.
- Transcriptomic analysis to characterize signaling pathway impacts.
- Use of suberanilohydroxamic acid (SAHA) to investigate histone deacetylase (HDAC) roles.
Main Results:
- Histones H3.1, H2A, and H2B identified as targets for RDC11, impacting histone complex formation.
- Differential epigenetic modifications on histone H3 and histone deacetylase gene expression observed between RDC11 and cisplatin.
- Distinct gene expression signatures and signaling pathway activations: cisplatin (p53, folate biosynthesis) vs. RDC11 (endoplasmic reticulum stress, trans-sulfuration).
- SAHA synergized with cisplatin but antagonized RDC11 activity.
Conclusions:
- Ruthenium complexes like RDC11 may have non-DNA direct targets, offering a distinct anticancer mechanism from platinum drugs.
- Identification of specific signaling pathways and epigenetic modifications provides a basis for differentiating organoruthenium compounds and platinum agents.
- This research clarifies the mode of action for organoruthenium compounds in oncotherapy.
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