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.
- SourceAvailable from: ncbi.nlm.nih.govChemical Reviews 08/2009; 109(8):3859-84. · 41.30 Impact Factor
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ABSTRACT: Apoptosis, or programmed cell death, has an essential role in controlling cell number in many developmental and physiological settings and in chemotherapy-induced tumour-cell killing. It is a genetically regulated biological process, guided by the ratio of proapoptotic and antiapoptotic proteins. Recently, inducers of apoptosis have been used in cancer therapy. Several studies have attempted to induce apoptosis by triggering the tumour-necrosis-factor-related apoptosis-inducing ligand receptor and the BCL2 family of proteins, and others have targeted the caspases, and proteins that inhibit apoptosis. Most of these therapies are still in preclinical development because of their low efficacy and susceptibility to drug resistance, but some of them have shown promising results. In this article, we review the development and clinical efficacy of proapoptotic drugs that have shown promise.The Lancet Oncology 01/2004; 4(12):721-9. · 25.12 Impact Factor
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ABSTRACT: Patterns of cell death have been divided into apoptosis, which is actively executed by specific proteases, the caspases, and accidental necrosis. However, there is now accumulating evidence indicating that cell death can occur in a programmed fashion but in complete absence and independent of caspase activation. Alternative models of programmed cell death (PCD) have therefore been proposed, including autophagy, paraptosis, mitotic catastrophe, and the descriptive model of apoptosis-like and necrosis-like PCD. Caspase-independent cell death pathways are important safeguard mechanisms to protect the organism against unwanted and potential harmful cells when caspase-mediated routes fail but can also be triggered in response to cytotoxic agents or other death stimuli. As in apoptosis, the mitochondrion can play a key role but also other organelles such as lysosomes and the endoplasmic reticulum have an important function in the release and activation of death factors such as cathepsins, calpains, and other proteases. Here we review the various models of PCD and their death pathways at molecular and organelle level and discuss the relevance of the growing knowledge of caspase-independent cell death pathways for cancer.Clinical Cancer Research 06/2005; 11(9):3155-62. · 7.84 Impact Factor