title: DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex.
abstract: The dinuclear copper(II) complex [Cu2{bcmp(-H)}(μ-OH)](NO3)2·H2O (1, bcmp=2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol) has been synthesized and characterized by electrospray ionization mass spectrometry, potentiometric titration and cyclovoltammetry. The X-ray structure of the analogous perchlorate salt [Cu2{bcmp(-H)}(μ-OH)](ClO4)2·2.5H2O (2) was determined. Cytotoxicity studies showed very promising activity of 1 against various pancreatic tumor cell lines with IC50 values comparable or even lower than those of cisplatin. The Cu complex displayed low toxicity against a human non-tumor cell line (HEK 293) demonstrating selectivity for cancer cells. 1 converts supercoiled pUC19 plasmid DNA into the nicked form at micromolar concentrations in the absence of added reductants. A detailed kinetic study on the hydrolysis of the DNA model bis(2,4-dinitrophenyl) phosphate (BDNPP) has been performed. 1 hydrolyses BDNPP with a second order rate constant of 0.047 M s(-1) at pH 8 and 40 °C. Finally, single cell electrophoresis (comet assay) and fluorescence microscopy analysis showed that 1 interacts with cellular DNA and induces apoptotic cell death of Capan-1 pancreatic cancer cells. Western blotting analysis indicated that the Cu complex activates the p53 dependent pathway of apoptosis.
authors: School of Chemistry, National University of Ireland, Galway, Ireland.
authors: Diego
authors: D
authors: Montagner
authors: Dipartimento di Scienze del Farmaco, Universita' degli Studi di Padova, Padova, Italy.
authors: Valentina
authors: V
authors: Gandin
authors: Dipartimento di Scienze del Farmaco, Universita' degli Studi di Padova, Padova, Italy.
authors: Cristina
authors: C
authors: Marzano
authors: School of Chemistry, National University of Ireland, Galway, Ireland. Electronic address: andrea.erxleben@nuigalway.ie.
authors: Andrea
authors: A
authors: Erxleben
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D020552:Comet Assay; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011199:Potentiometry; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D056831:Coordination Complexes
keywords: Copper; Cytotoxicity; DNA damage; Metallodrugs