QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.089342v1 315/3/1403    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gaiddon, C. Articles by Loeffler, J. P. Search for Related Content PubMed PubMed Citation Articles by Gaiddon, C. Articles by Loeffler, J. P.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Ruthenium (II)-Derived Organometallic Compounds Induce Cytostatic and Cytotoxic Effects on Mammalian Cancer Cell Lines through p53-Dependent and p53-Independent Mechanisms

Institut National de la Sante et de la Recherche Medicale U692-Université Louis Pasteur, Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France

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 Np73, 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.

Address correspondence to: Christian Gaiddon, U692 INSERM-Université Louis Pasteur, Signalisations Moléculaires et Neurodégénérescence, 11 rue Human, 67085 Strasbourg, France. E-mail: gaiddon{at}neurochem.u-strasbg.fr

This article has been cited by other articles:

				X. Meng, M. L. Leyva, M. Jenny, I. Gross, S. Benosman, B. Fricker, S. Harlepp, P. Hebraud, A. Boos, P. Wlosik, et al. A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP Cancer Res., July 1, 2009; 69(13): 5458 - 5466. [Abstract] [Full Text] [PDF]