Inhibition of Na+/K+-ATPase and cytotoxicity of a few selected gold(III) complexes

Na+/K+-ATPase is in charge of maintaining the ionic and osmotic intracellular balance by using ATP as an energy source to drive excess Na+ ions out of the cell in exchange for K+ ions. We explored whether three representative cytotoxic gold(III) compounds might interfere with Na+/K+-ATPase and cause its inhibition at pharmacologically relevant concentrations. The tested complexes were [Au(bipy)(OH)2][PF6] (bipy = 2,2′-bipyridine), [Au(pydmb-H)(CH3COO)2] (pydmb-H = deprotonated 6-(1,1-dimethylbenzyl)-pyridine), and [Au(bipydmb-H)(OH)][PF6] (bipydmb-H = deprotonated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine). We found that all of them caused a pronounced and similar inhibition of Na+/K+-ATPase activity. Inhibition was found to be non-competitive and reversible. Remarkably, treatment with cysteine resulted in reversal or prevention of Na+/K+-ATPase inhibition. It is very likely that the described effects may contribute to the overall cytotoxic profile of these gold complexes.

The tested complexes were [Au(bipy)(OH)2][PF6], [Au(pydmb-H)(CH3COO)2][PF6], and [Au(bipyc-H)(OH)(CH3)2][PF6]. We found that all of them caused a pronounced and similar inhibition of human and porcine Na+/K+-ATPase activity. Inhibition was found to be non-competitive and reversible. Treatment with cysteine resulted in reversal or prevention of Na+/K+-ATPase inhibition.Figure optionsDownload as PowerPoint slide