Anticancer Activity of Silver–N‐Heterocyclic Carbene Complexes: Caspase‐Independent Induction of Apoptosis via Mitochondrial Apoptosis‐Inducing Factor (AIF)

ChemMedChem - Tập 7 Số 5 - Trang 805-814 - 2012
Laure Eloy1, Anne‐Sophie Jarrousse2, Marie‐Laure Teyssot3, Arnaud Gautier3, Laurent Morel2, Claude Jolivalt4, Thierry Cresteil1, Sylvain Roland5
1Institut de Chimie des Substances Naturelles, UPR CNRS 2301, Avenue de la Terrasse, 91198 Gif‐sur‐Yvette (France)
2Laboratoire GReD, UMR 6247 CNRS, INSERM U931, Clermont Université, 24 avenue des Landais, 63177 Aubière CEDEX (France)
3Laboratoire SEESIB, UMR 6504 CNRS, Clermont Université, 24 avenue des Landais, 63177 Aubière CEDEX (France)
4Laboratoire Charles Friedel, UMR CNRS 7223, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris cedex 05, France
5Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, UPMC-Université Paris 6, 4 place Jussieu, 75252 Paris CEDEX 05 (France)

Tóm tắt

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 IC50 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 (ΔΨm) 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.

Từ khóa


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ChemMedChem

Tập 7 Số 5

805-814

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