Mechanisms of cytotoxicity and antitumor activity of gold(Ⅰ) phosphine complexes: the possible role of mitochondria

摘要

Well known for their clinical anti-arthritic properties, gold-based drugs have also attracted interest as potential antitumor agents with gold(Ⅰ) phosphine derivatives being among the most active in vivo. Auranofin, a linear tetraacetylthioglucose gold(Ⅰ) phosphine complex, increased the life span of mice inoculated with P388 leukaemia, inhibited DNA polymerases and was preferentially cytotoxic to cells with altered mitochondria. Triethylphosphine gold(Ⅰ) chloride inhibited tumor colony formation in vitro, reacted with DNA, and inhibited oxidative phosphorylation, ATP production and the viability of isolated rat hepatocytes. Bis[1,2-bis(diphenylphosphino)ethane]gold(Ⅰ) chloride ([Au(dppe)_2]Cl) had reproducible and significant antitumor activity in a number of murine tumor models in vivo. [Au(dppe)_2]Cl also inhibited tumor colony formation in vitro, formed DNA strand beaks, induced DNA-protein cross links and had antimitochondrial effects on P388 leukemia cells and isolated hepatocytes. Tetrahedral Au(Ⅰ)complexes of bidentate pyridyl phosphines have shown promising in vitro and in vivo antitumor properties that are determined by their drug lipophilicity. Although the exact intracellular targets responsible for their antitumor activity are unclear, gold(Ⅰ) phosphines are directly cytotoxic and many appear to have antimitochondrial activity. Optimization of their hydrophilic-lipophilic balance may be key to improving their selectivity for tumor mitochondria versus oxidative phosphorylation pathways of normal cells.