Cytotoxicity, DNA damage, and cell cycle perturbations induced by two representative gold(III) complexes in human leukemic cells with different cisplatin sensitivity

The gold(III) complexes [Au(phen)Cl-2]Cl and [Au(dien)Cl]Cl were recently s hown to exert important cytotoxic effects in vitro on human tumor cell line s. To elucidate the biochemical mechanisms leading to cell death, the effec ts produced by these gold(III) complexes on the leukemic CCRF-CEM cell line -either sensitive (CCRF-CEM) or resistant to cisplatin (CCRF-CEM/CDDP)-were analyzed in detail by various techniques. For comparison purposes the effe cts produced by equitoxic concentrations of cisplatin were also analyzed. F irst, the dependence of the IC50 values of either complex on the incubation time was investigated. Cytotoxicity experiments confirmed that both gold(I II) compounds retain their efficacy against the cisplatin-resistant line: o nly minimal cross-resistance with cisplatin was detected. Notably, [Au(phen )Cl-2]Cl is more cytotoxic than [Au(dien)Cl]Cl-2, with IC50 values of 7.4 a nd 6.0 M at 24 and 72 h, respectively, on the resistant line. Results of th e COMET assay point out that both gold(III) complexes directly damage nucle ar DNA. Remarkably, DNA damage inferred by either gold(III) complex in the two cell lines is larger than that produced by equitoxic cisplatin concentr ations. Finally, the effects that either gold(III) complex produces on the cell cycle were investigated by flow cytometry. It was found that both comp lexes cause only moderate and transient cell cycle perturbations. Larger ce ll cycle perturbations are induced by equitoxic concentrations of cisplatin . The implications of the present results for the mechanism of action of cy totoxic gold(III) complexes are discussed.