title: Anticancer activity of silver-N-heterocyclic carbene complexes: caspase-independent induction of apoptosis via mitochondrial apoptosis-inducing factor (AIF).
abstract: Fourteen silver(I) complexes bearing N-heterocyclic carbene (NHC) ligands were prepared and evaluated for anticancer activity. Some of these were found to exhibit potent antiproliferative activity toward several types of human cancer cell lines, including drug-resistant cell lines, with IC(50) values in the nanomolar range. An initial investigation into the mechanism of cell death induced by this family of silver(I) complexes was carried out. Cell death was shown to result from the activation of apoptosis without involvement of primary necrosis. In HL60 cells, silver-NHCs induce depolarization of the mitochondrial membrane potential (ΔΨ(m)) and likely allow the release of mitochondrial proteins to elicit early apoptosis. This effect is not related to the overproduction of reactive oxygen species (ROS). In addition, apoptosis is not associated with the activation of caspase-3, but is triggered by the translocation of apoptosis-inducing factor (AIF) and caspase-12 from mitochondria and the endoplasmic reticulum, respectively, into the nucleus to promote DNA fragmentation and ultimately cell death. No modification in cell-cycle distribution was observed, indicating that silver-NHCs are not genotoxic. Finally, the use of a fluorescent complex showed that silver-NHCs target mitochondria. Altogether, these results demonstrate that silver-NHCs induce cancer cell death independent of the caspase cascade via the mitochondrial AIF pathway.
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR CNRS 2301, Gif-sur-Yvette, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Eloy
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jarrousse
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Teyssot
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gautier
authors.forename: Laurent
authors.initials: L
authors.lastname: Morel
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Roland
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008954:Models, Biological; D015394:Molecular Structure; D012834:Silver / Q000494:pharmacology
chemical_list: D051033:Apoptosis Inducing Factor; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; C030011:carbene; D012834:Silver; D020169:Caspases; D008697:Methane