Mitochondrial permeability transition induced by dinuclear gold(I)-carbene complexes: potential new antimitochondrial antitumour agents.
Seven dinuclear gold(I) complexes of bidentate N-heterocyclic carbene ligands have been evaluated for their ability to induce mitochondrial membrane permeabilisation (MMP) in isolated rat liver mitochondria. Six of the compounds, at concentrations of 10 microM, induced Ca(2+)-sensitive MMP as evidenced by mitochondrial swelling. In the absence of low concentrations of exogenous Ca(2+), the compounds were either inactive or their activity was significantly decreased. The mitochondrial swelling was completely blocked by the addition of cyclosporin A, a well established inhibitor of the mitochondrial permeability transition pore (MPT) that is believed to be responsible for MMP. The rates and levels of uptake of these compounds into mitochondria were estimated by measuring mitochondrial Au levels using inductively coupled plasma optical emission spectroscopy. Significant differences were found in the levels at which the different compounds accumulated in the mitochondria, but these differences did not correlate with the rate at which they induced mitochondrial swelling. These results suggest that the mechanism by which MMP is induced by these lipophilic cationic Au(I)-carbene complexes is not purely a function of the level of compound accumulation. Instead, a more specific mechanism, possibly involving disruption of the function of a particular enzyme, or interaction with a MPT component, appears to be more likely.
Barnard
Peter J
PJ
Department of Chemistry, School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Perth 6009, Australia.
Baker
Murray V
MV
Berners-Price
Susan J
SJ
Day
David A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D017612:Gold Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006838:Hydrocarbons; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects; D051381:Rats
D000970:Antineoplastic Agents; D017612:Gold Compounds; D006838:Hydrocarbons; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C030011:carbene; D016572:Cyclosporine; D008697:Methane