title: Acridin-3,6-dialkyldithiourea hydrochlorides as new photosensitizers for photodynamic therapy of mouse leukemia cells.
abstract: Acridin-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) have been evaluated as a new group of photosensitizers (PSs) for photodynamic antitumor therapy (PDT). Mouse leukemia cells L1210 were used for testing of AcrDTUs as the new PSs. The irradiation (UV-A light (365 nm), 1.05 J/cm(2)) increased cytotoxicity of all derivatives against L1210 cells more than ten times. The highest photocytotoxicity was found for propyl-AcrDTU with IC50=0.48±0.03 μM after 48 h incubation. A generation of the superoxide radical anion upon UV-A irradiation of propyl-AcrDTU was confirmed by in situ photochemical EPR experiments. To explain a mechanism of photocytotoxic action of AcrDTUs, an intracellular distribution of propyl-AcrDTU has been studied. It was found that AcrDTU in non-irradiated cells was not present in their nucleus but in the lysosomes and partly in the mitochondria, and sequestration of propyl-AcrDTU was dependent on pH in lysosomes. After irradiation, the cell death was induced by oxidative damage of lysosomal and mitochondrial membranes. Concerning the cell cycle, flow cytometry after PDT with propyl-AcrDTU showed a significant increase of the cells in the subG0 phase. Observed signs of necrosis, apoptosis, and autophagy indicate that PDT/AcrDTU leads to multiple cell death types (caspase independent apoptosis, necrosis, and autophagy).
authors.affiliation: Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic.
authors.forename: A
authors.initials: A
authors.lastname: Cisáriková
authors.affiliation: Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic.
authors.forename: Z
authors.initials: Z
authors.lastname: Barbieriková
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Pavol Jozef Šafárik University, Moyzesova 11, 041 01 Košice, Slovak Republic.
authors.forename: L
authors.initials: L
authors.lastname: Janovec
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Pavol Jozef Šafárik University, Moyzesova 11, 041 01 Košice, Slovak Republic.
authors.forename: J
authors.initials: J
authors.lastname: Imrich
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava, Slovak Republic.
authors.forename: L
authors.initials: L
authors.lastname: Hunáková
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovak Republic.
authors.forename: Z
authors.initials: Z
authors.lastname: Bačová
authors.affiliation: Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic. Electronic address: helena.paulikova@stuba.sk.
authors.forename: H
authors.initials: H
authors.lastname: Paulíková
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*
chemical_list: D000166:Acridines; D017319:Photosensitizing Agents
keywords: Acridines; Anticancer drugs; Photodynamic therapy; Photosensitizers