title: Detailed Biological Profiling of a Photoactivated and Apoptosis Inducing pdppz Ruthenium(II) Polypyridyl Complex in Cancer Cells.
abstract: Ruthenium polypyridyl complexes show great promise as new photodynamic therapy (PDT) agents. However, a lack of detailed understanding of their mode of action in cells poses a challenge to their development. We have designed a new Ru(II) PDT candidate that efficiently enters cells by incorporation of the lipophilic aromatic pdppz ([2,3-h]dipyrido[3,2-a:2',3'-c]phenazine) ligand and exhibits photoactivity through incorporation of 1,4,5,8-tetraazaphenanthrene ancillary ligands. Its photoreactivity toward biomolecules was studied in vitro, where light activation caused DNA cleavage. Cellular internalization occurred via an energy dependent mechanism. Confocal and transmission electron microscopy revealed that the complex localizes in various organelles, including the mitochondria. The complex is nontoxic in the dark, with cellular clearance within 96 h; however, upon visible light activation it induces caspase-dependent and reactive-oxygen-species-dependent apoptosis, with low micromolar IC50 values. This investigation greatly increases our understanding of such systems in cellulo, aiding development and realization of their application in cancer therapy.
authors.affiliation: †School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cloonan
authors.affiliation: ‡School of Chemistry and Trinity Biomedical Sciences Institute, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Robert B P
authors.initials: RB
authors.lastname: Elmes
authors.affiliation: †School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: MariaLuisa
authors.initials: M
authors.lastname: Erby
authors.affiliation: †School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Bright
authors.affiliation: ‡School of Chemistry and Trinity Biomedical Sciences Institute, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Fergus E
authors.initials: FE
authors.lastname: Poynton
authors.affiliation: †School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Nolan
authors.affiliation: §School of Chemistry and Chemical Biology, University College Dublin, Dublin 2, Ireland.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Quinn
authors.affiliation: ‡School of Chemistry and Trinity Biomedical Sciences Institute, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Thorfinnur
authors.initials: T
authors.lastname: Gunnlaugsson
authors.affiliation: †School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D020552:Comet Assay; D053837:DNA Cleavage / Q000187:drug effects; D006801:Humans; D008027:Light; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011725:Pyridines; D017382:Reactive Oxygen Species; D017975:Ruthenium Compounds