title: Synchrotron X-Ray Fluorescence Nanoprobe Reveals Target Sites for Organo-Osmium Complex in Human Ovarian Cancer Cells.
abstract: A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub-cellular distribution of [Os(η6-p-cym)(Azpy-NMe2)I]+(p-cym=p-cymene, Azpy-NMe2=2-(p-[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X-ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death. These data are consistent with the ability of 1 to induce rapid bursts of reactive oxygen species and especially superoxide formed in the first step of O2reduction in mitochondria. Such metabolic targeting differs from the action of Pt drugs, offering promise for combatting Pt resistance, which is a current clinical problem.
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0002-9522-0019
authors.initials: C
authors.lastname: Sanchez-Cano
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Isolda
authors.identifier: http://orcid.org/0000-0003-3847-4626
authors.initials: I
authors.lastname: Romero-Canelón
authors.affiliation: ID16A beamline, ESRF, The European Synchrotron, 71 Avenue des Martyrs, 3800, Grenoble, France.
authors.forename: Yang
authors.identifier: http://orcid.org/0000-0001-5318-5385
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Ian J
authors.identifier: http://orcid.org/0000-0002-8895-2342
authors.initials: IJ
authors.lastname: Hands-Portman
authors.affiliation: ID16A beamline, ESRF, The European Synchrotron, 71 Avenue des Martyrs, 3800, Grenoble, France.|Inserm, U836, equipe 6, "Rayonnement synchrotron et recherches medicales", Grenoble, Institut des Neurosciences, 38054, Grenoble, France.
authors.forename: Sylvain
authors.identifier: http://orcid.org/0000-0001-6355-7592
authors.initials: S
authors.lastname: Bohic
authors.affiliation: ID16A beamline, ESRF, The European Synchrotron, 71 Avenue des Martyrs, 3800, Grenoble, France.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-4129-9091
authors.initials: P
authors.lastname: Cloetens
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Peter J
authors.identifier: http://orcid.org/0000-0001-9160-1941
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000081007:Cymenes; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D039821:Monoterpenes / Q000737:chemistry; D049329:Nanostructures / Q000737:chemistry*; D009992:Osmium / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017356:Synchrotrons
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000081007:Cymenes; D005456:Fluorescent Dyes; D039821:Monoterpenes; D017382:Reactive Oxygen Species; C007210:4-cymene; D009992:Osmium
keywords: X-ray fluorescence; bioinorganic chemistry; elemental mapping; metallodrugs; organometallic complexes