title: Visualising gold inside tumour cells following treatment with an antitumour gold(I) complex.
abstract: Gold(I) phosphine complexes, such as [Au(d2pype)(2)]Cl, (1, where d2pype is 1,2-bis(di-2-pyridyl phosphinoethane)), belong to a class of promising chemotherapeutic candidates that have been shown to be selectively toxic to tumourigenic cells, and may act via uptake into tumour cell mitochondria. For a more holistic understanding of their mechanism of action, a deeper knowledge of their subcellular distribution is required, but to date this has been limited by a lack of suitable imaging techniques. In this study the subcellular distribution of gold was visualised in situ in human breast cancer cells treated with 1, using nano-scale secondary ion mass spectrometry. NanoSIMS ion maps of (12)C(14)N(-), (31)P(-), (34)S(-) and (197)Au(-) allowed, for the first time, visualisation of cellular morphology simultaneously with subcellular distribution of gold. Energy filtered transmission electron microscopy (EFTEM) element maps for gold were also obtained, allowing for observation of nuclear and mitochondrial morphology with excellent spatial resolution, and gold element maps comparable to the data obtained with NanoSIMS. Following 2 h treatment with 1, the subcellular distribution of gold was associated with sulfur-rich regions in the nucleus and cytoplasm, supporting the growing evidence for the the mechanism of action of Au(I) compounds based on inhibition of thiol-containing protein families, such as the thioredoxin system. The combination of NanoSIMS and EFTEM has broader applicability for studying the subcellular distribution of other types of metal-based drugs.
authors.affiliation: School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Wedlock
authors.forename: Matt R
authors.initials: MR
authors.lastname: Kilburn
authors.forename: John B
authors.initials: JB
authors.lastname: Cliff
authors.forename: Luis
authors.initials: L
authors.lastname: Filgueira
authors.forename: Martin
authors.initials: M
authors.lastname: Saunders
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Berners-Price
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006046:Gold / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006651:Histocytochemistry / Q000379:methods; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D046529:Microscopy, Electron, Transmission; D057054:Molecular Imaging; D036103:Nanotechnology; D010720:Phosphines / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010720:Phosphines; D006046:Gold