title: Nitroimidazole derivatives of polypyridyl ruthenium complexes: Towards understanding their anticancer activity and mode of action.
abstract: The mechanism of cell death induced by the ruthenium polypyridyl complexes comprising two 4,7-diphenyl-1,10-phenanthroline ligands as well as one unmodified 2,2'-bipyridyl or modified with 2-nitroimidazole moiety attached by shorter (C3H6) or longer (C6H12) linker was investigated. Cytotoxicity and proliferation assays revealed that the studied Ru polypyridyl complexes are more toxic against human pancreas carcinoma PANC-1 cell line than normal human keratinocytes HaCaT with IC50of 3-5μM. The Ru complexes despite accumulation in mitochondria do not lead to mitochondrial disfunction, though decreasing of mitochondrial Ca2+causes mitochondria membrane hyperpolarization. The Ru polypyridyl conjugates induce some phenotypical characteristic of apoptosis, such as condensation of chromatin or phosphatidylserine translocation, however no caspase or calpain activation in the studied cell lines was observed, indicating that detected cell death does not occur via mitochondria- or ER-activated pathways. Caspase-independent cell death is caused by enormous ROS formation, mainly hydrogen peroxide and peroxyl radicals as well as by intracellular Ca2+homeostasis disruption. Accumulation of the Ru compounds inhibits the completion of DNA synthesis, arresting cells in S-phase of cell cycle.
authors.affiliation: Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Mazuryk
authors.affiliation: Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland; Institute of Organic and Analytical Chemistry, University of Orléans, UMR-CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Oksana
authors.initials: O
authors.lastname: Krysiak-Foria
authors.affiliation: Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland; Institute of Organic and Analytical Chemistry, University of Orléans, UMR-CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Żak
authors.affiliation: Institute of Organic and Analytical Chemistry, University of Orléans, UMR-CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Suzenet
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Ptak-Belowska
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brzozowski
authors.affiliation: Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Stochel
authors.affiliation: Department of Inorganic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. Electronic address: brindell@chemia.uj.edu.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Brindell
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology*; D010618:Phenanthrolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012428:Ruthenium / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D010618:Phenanthrolines; D017382:Reactive Oxygen Species; D012428:Ruthenium; D002118:Calcium; C025205:1,10-phenanthroline
keywords: Apoptosis; Cytotoxicity; Nitroimidazole; ROS; Ruthenium polypyridyl complex