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 31P 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 compoundwas found to exhibit strong cytotoxicity, showing 85 fold greater toxicity than cisplatin (IC50 = 0.45 μM vs IC50 = 39.16 for cisplatin at 24 h) 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.
Synthesis, properties, and antitumor effects of a new mixed phosphine gold(I) compound in human colon cancer cells
LUPIDI, Giulio;BRAMUCCI, Massimo;QUASSINTI, Luana;PETTINARI, Riccardo;MARCHETTI, Fabio;PETTINARI, Claudio
2013-01-01
Abstract
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 31P 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 compoundwas found to exhibit strong cytotoxicity, showing 85 fold greater toxicity than cisplatin (IC50 = 0.45 μM vs IC50 = 39.16 for cisplatin at 24 h) 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
