The
antineoplastic potential of a new stable mixed
phosphine gold(I) complex containing tris(tert-butyl)
phosphine (tBu3P) and bis(diphenylphosphino)
ethene (dppet), namely [Au(tBu3P)(dppet)Cl], has been investigated in the human
colon cancer HCT-116 cell line. The (31)P NMR
solution study, confirms the structural features observed in the solid state and, in addition, indicates partial formation of dinuclear cationic [Au(tBu3P)2](+) and [Au(dppet)2](+) species. The ionic character and strong Au-P bonds of this
gold(I) species are similar to those of the most active antitumor
gold compounds so far studied. The title compound was found to exhibit strong cytotoxicity, showing 85 fold greater toxicity than
cisplatin (IC50=0.45μM vs IC50=39.16 for
cisplatin at 24h) on the HCT-116 line. The cytotoxic effects were, at least partly, mediated by the induction of apoptotic cell death as evidenced by the sub-G1 cell accumulation, oligonucleosomal DNA fragmentation,
caspase-3 activation and the release of
cytochrome c from the mitochondria. The
gold(I) compound showed little interaction with
DNA measured through fluorescence quenching studies with
calf thymus DNA. The inhibitory effect of the
gold(I) compound on intracellular redox
proteins has been also observed in pretreated HCT-116 cells. The compound was particularly effective in inhibiting
thioredoxin reductase, that is likely responsible for the increased ROS production, and subsequent apoptosis induction via the mitochondrial pathway.