Targeting the mitochondrial cell death pathway with gold compounds

There is much recent evidence showing that mitochondria play a critical role in the regulation of apoptosis (programmed cell death), making them an attractive target for the design of new anticancer drugs. A variety of different strategies targeting mitochondria for cancer therapy have been described in recent literature. Several different classes of gold-based compounds (in both Au(I) and Au(III) oxidation states) have attracted interest as potential antitumour agents and there is evidence that many act by mechanisms involving mitochondrial cell death pathways. Two distinct classes of Au(I) phosphine complexes display antitumour properties, these having either linear two-coordinate, or tetrahedral four-coordinate geometries. Both classes appear to target mitochondria, but different mechanisms are likely to be involved, related to their differing propensity to undergo ligand exchange reactions with biological ligands. The anti-arthritic Au(I) phosphine drug, auranofin, has been shown to induce apoptosis via selective inhibition of the mitochondrial isoform of thioredoxin reductase, an enzyme which has emerged as a potential new drug target. Gold(I) compounds are among the most potent known inhibitors of thioredoxin reductase, attributable to binding of Au(I) to the redox-active selenocysteine residue. On the other hand [Au(dppe)(2)](+), and related tetrahedral Au(I) phosphine complexes, do not undergo ligand exchange reactions as readily as two-coordinate linear Au(I) complexes. Their antitumour activity may stem from the lipophilic, cationic properties, as for other delocalised lipophilic cations that accumulate in mitochondria.