title: Induction of caspase 8 and reactive oxygen species by ruthenium-derived anticancer compounds with improved water solubility and cytotoxicity.
abstract: Organometallic compounds which contain metals, such as ruthenium or gold, have been investigated as a replacement for platinum-derived anticancer drugs. They often show good antitumor effects, but the identification of their precise mode of action or their pharmacological optimization is still challenging. We have previously described a class of ruthenium(II) compounds with interesting anticancer properties. In comparison to cisplatin, these molecules have lower side effects, a reduced ability to interact with DNA, and they induce cell death in absence of p53 through CHOP/DDIT3. We have now optimized these molecules by improving their cytotoxicity and their water solubility. In this article, we demonstrate that by changing the ligands around the ruthenium we modify the ability of the compounds to interact with DNA. We show that these optimized molecules reduce tumor growth in different mouse models and retain their ability to induce CHOP/DDIT3. However, they are more potent inducers of cancer cell death and trigger the production of reactive oxygen species and the activation of caspase 8. More importantly, we show that blocking reactive oxygen species production or caspase 8 activity reduces significantly the activity of the compounds. Altogether our data suggest that water-soluble ruthenium(II)-derived compounds represent an interesting class of molecules that, depending on their structures, can target several pro-apoptotic signaling pathways leading to reactive oxygen species production and caspase 8 activation.
authors.affiliation: UMRS INSERM, Strasbourg, France.
authors.forename: Vania
authors.initials: V
authors.lastname: Vidimar
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Meng
authors.forename: Marcelina
authors.initials: M
authors.lastname: Klajner
authors.forename: Cynthia
authors.initials: C
authors.lastname: Licona
authors.forename: Ludivine
authors.initials: L
authors.lastname: Fetzer
authors.forename: Sébastien
authors.initials: S
authors.lastname: Harlepp
authors.forename: Pascal
authors.initials: P
authors.lastname: Hébraud
authors.forename: Marjorie
authors.initials: M
authors.lastname: Sidhoum
authors.forename: Claude
authors.initials: C
authors.lastname: Sirlin
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.forename: Georg
authors.initials: G
authors.lastname: Mellitzer
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
authors.forename: Michel
authors.initials: M
authors.lastname: Pfeffer
authors.forename: Christian
authors.initials: C
authors.lastname: Gaiddon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053181:Caspase 8 / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D017975:Ruthenium Compounds; D014867:Water; D053181:Caspase 8