title: A platinum blue complex exerts its cytotoxic activity via DNA damage and induces apoptosis in cancer cells.
abstract: Here, we describe the characteristics of a Pt-blue complex [Pt4(2-atp)8(H2O)(OH)] (2-atp: 2-aminothiophenol) as a prodrug for its DNA-binding properties and its use in cancer therapy. The nature of the interaction between the Pt-blue complex and DNA was evaluated based on spectroscopic measurements, the electronic absorption spectra, thermal behavior, viscosity, fluorometric titration, and agarose gel electrophoresis. Our results suggested that the compound was able to partially intercalate DNA and appeared to induce both single- and double-stranded breaks (DBS) on DNA in vitro, but no DSBs in cells. The ability of the compound to induce DNA damage was dependent on reactive oxygen species (ROS) in vitro. There was also elevated formation of ROS and SOD expression in response to drug treatment in cell culture. The complex was found to be more cytotoxic to cancer cells in comparison with noncancer controls using WST-1 assay. The mean of cell death was determined to be apoptosis as assessed via biochemical, morphological, and molecular observations, including DNA condensation/fragmentation analysis, live cell imaging microscopy, TUNEL analyses, and increase in the levels of pro-apoptotic genes such as Bag3, Bak, Bik, Bmf, and Hrk. Hence, the Pt-blue complex under study grants premise for further studies.
authors.affiliation: TUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Gebze/Kocaeli, Turkey.
authors.forename: Zelal
authors.initials: Z
authors.lastname: Adiguzel
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, Faculty of Engineering, Atilim University, Ankara, Turkey.
authors.forename: Seniz
authors.initials: S
authors.lastname: Ozalp-Yaman
authors.affiliation: Sentegen Biotech, Bilkent Cyberpark, Çankaya/Ankara, Turkey.
authors.forename: Gokalp
authors.initials: G
authors.lastname: Celik
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, Faculty of Engineering, Atilim University, Ankara, Turkey.
authors.forename: Safia
authors.initials: S
authors.lastname: Salem
authors.affiliation: Medical School, Koc University, Sariyer/Istanbul, Turkey.
authors.forename: Tugba
authors.initials: T
authors.lastname: Bagci-Onder
authors.affiliation: Medical School, Koc University, Sariyer/Istanbul, Turkey.
authors.forename: Filiz
authors.initials: F
authors.lastname: Senbabaoglu
authors.affiliation: TUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Gebze/Kocaeli, Turkey.
authors.forename: Yüksel
authors.initials: Y
authors.lastname: Cetin
authors.affiliation: TUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Gebze/Kocaeli, Turkey.
authors.forename: Ceyda
authors.identifier: 0000-0002-8936-3267
authors.initials: C
authors.lastname: Acilan
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; C005464:2-aminothiophenol
keywords: DNA damage; anticancer drugs; apoptosis; platinum blue complexes; reactive oxygen species