title: Synthesis, properties, and antitumor effects of a new mixed phosphine gold(I) compound in human colon cancer cells.
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 (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.
authors: School of Pharmacy, Molecular Biological Section, Via Madonna delle Carceri, 62032 Camerino, Italy.
authors: Giulio
authors: G
authors: Lupidi
authors: Luca
authors: L
authors: Avenali
authors: Massimo
authors: M
authors: Bramucci
authors: Luana
authors: L
authors: Quassinti
authors: Riccardo
authors: R
authors: Pettinari
authors: Hala K
authors: HK
authors: Khalife
authors: Hala
authors: H
authors: Gali-Muhtasib
authors: Fabio
authors: F
authors: Marchetti
authors: Claudio
authors: C
authors: Pettinari
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017612:Gold Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010720:Phosphines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D017612:Gold Compounds; D007306:Insecticides; D010720:Phosphines; D017382:Reactive Oxygen Species; C044646:phosphine; D002945:Cisplatin