Abstract
The metallic compound cisplatin has been used for many years to treat various human cancers. Here, we describe the cytostatic and cytotoxic properties of a new class of organometallic compounds that contain a ruthenium (II) atom covalently linked to carbon and nitrogen atoms. We found that several ruthenium-derived compounds (RDCs) led to G1 arrest and induced apoptosis in tumor cell lines derived from glioblastomas, neuroblastomas, and lymphoid tumors at least as efficiently as cisplatin. We further analyzed the signaling pathways underlying these effects, and we showed that both RDCs and cisplatin induced p53 and p73 protein levels but with different intensities and kinetics. This accumulation of p53 and p73 proteins correlated with an increase in p21 and Bax expression, two p53 target genes linked to cell growth arrest and apoptosis. However, in contrast to cisplatin-induced apoptosis, overexpression of ΔNp73, a p53 and p73 dominant-negative isoform, only partly reduced RDC-induced apoptosis, suggesting p53-dependent and p53-independent modes of action. This observation was further confirmed by the ability of RDC to induce apoptosis in p53–/– cells. Altogether, this study highlights key cellular and molecular features of RDCs and suggests that further development of this new class of compounds may contribute to improve future chemotherapeutic protocols.
Footnotes
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This work was supported by the Centre National de la Recherche Scientifique, Association pour la Recherche sur le Cancer (no. 3288), La Ligue contre le Cancer (Comité du Bas-Rhin), and Association pour la Recherche et le Dé-veloppement de Moyens de Lutte contre les Maladies Neuro-Dégénératives (AREMANE).
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doi:10.1124/jpet.105.089342.
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ABBREVIATIONS: ATM, ataxia telangiectasia, mutated; ATR, ataxia telangiectasia, mutated and Rad-3-related; RDC, ruthenium-derived compound; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; PBS, phosphate-buffered saline; BSA, bovine serum albumin; GFP, green fluorescent protein; PAGE, polyacrylamide gel electrophoresis; FACS, fluorescence-activated cell sorting.
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↵1 Current affiliation: Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil 3430, Altérations Géniques des Cancers et Réponse Thérapeutique, Institut de Recherche des Cancers de l'Appareil Digestif, Hôpitaux Universitaires, Strasbourg, France.
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↵2 Current affiliation: Unité Mixte de Recherche 7513-Université de Strasbourg, Laboratoire de Synthèses Métallo-Induites, Strasbourg, France.
- Received May 10, 2005.
- Accepted September 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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