A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

¹UMRS692 INSERM, Signalisations Moléculaires et Neurodégénérescence, Université de Strasbourg; ²Institut de Chimie, UMR 7177 CNRS, Université de Strasbourg; ³EA 3430, Centre Paul Strauss, Université de Strasbourg; ⁴IPCMS, UMR 7504 CNRS; ⁵UMR 7178 IPHC-DSA, UdS, CNRS, ECPM; and ⁶UMRS682 INSERM, Université de Strasbourg, Strasbourg, France

^* To whom correspondence should be addressed. E-mail: gaiddon{at}neurochem.u-strasbg.fr.

	Abstract

Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other types of organometallic complexes, namely, some ruthenium-derived compounds (RDC), which would display cytotoxicity through different modes of action, might represent alternative therapeutic agents. We have studied both in vitro and in vivo the biological properties of RDC11, one of the most active compounds of a new class of RDCs that contain a covalent bond between the ruthenium atom and a carbon. We showed that RDC11 inhibited the growth of various tumors implanted in mice more efficiently than cisplatin. Importantly, in striking contrast with cisplatin, RDC11 did not cause severe side effects on the liver, kidneys, or the neuronal sensory system. We analyzed the mode of action of RDC11 and showed that RDC11 interacted poorly with DNA and induced only limited DNA damages compared with cisplatin, suggesting alternative transduction pathways. Indeed, we found that target genes of the endoplasmic reticulum stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in RDC11-treated cells. Induction of the transcription factor CHOP, a crucial mediator of endoplasmic reticulum stress apoptosis, was also confirmed in tumors treated with RDC11. Activation of CHOP led to the expression of several of its target genes, including proapoptotic genes. In addition, the silencing of CHOP by RNA interference significantly reduced the cytotoxicity of RDC11. Altogether, our results led us to conclude that RDC11 acts by an atypical pathway involving CHOP and endoplasmic reticulum stress, and thus might provide an interesting alternative for anticancer therapy. [Cancer Res 2009;69(13):5458–66]

Key Words: Ruthenium, anticancer therapy, endoplasmic reticulum stress, DNA damages, toxicity, glioblastoma, melanoma, CHOP, p53