title: Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy.
abstract: The photoeffect of new proflavine derivatives with DNA-binding and antitumour activities, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides (AcrDIMs), was studied to evaluate them as potential photosensitizers for photodynamic antitumor therapy. EPR measurements showed that superoxide radical anion and singlet oxygen were produced upon irradiation of AcrDIMs with UV-A light (>300nm) in the presence of molecular oxygen. This indicates that AcrDIMs may act as photosensitizers. The most active pentyl-AcrDIM and hexyl-AcrDIM displayed photocytotoxic effect toward the mouse lymphocytic leukemia cell line L1210 and human ovarian cancer cells A2780. Antitumor activity of pentyl-AcrDIM increased as high as about 12 times (72h incubation) after irradiation of A2780 cells (365nm, 1.05J/cm(2)). The photocytotoxicity seems to be associated with oxidative stress. Concerning the cell cycle, flow cytometry showed an arrest in the S-phase already 4h after irradiation. In a comet assay, no genotoxicity of AcrDIMs was found. Typical morphologic changes and formation of DNA-ladders indicated induction of apoptotic cell death, though no activation of caspase-3 was observed. Investigation of intracellular localization of pentyl-AcrDIM confirmed its partial accumulation in mitochondria and lysosomes. After irradiation of the A2780 cells, colocalization of pentyl-AcrDIM with monodansylcadaverine, a lysosomal dye, was proven, suggesting that lysosomes in the irradiated cells may be involved in the cell death.
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: L
authors.initials: L
authors.lastname: Cižeková
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: Grolmusová
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: Z
authors.initials: Z
authors.lastname: Ipóthová
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 Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic.
authors.forename: V
authors.initials: V
authors.lastname: Brezová
authors.affiliation: Cancer Research Institute, Vlárska 7, 83391 Bratislava, Slovak Republic.
authors.forename: L'
authors.initials: L
authors.lastname: Hunáková
authors.affiliation: Department of Organic Chemistry, Pavol Jozef Šafárik University, Moyzesova 11, 041 57 Košice, Slovak Republic.
authors.forename: J
authors.initials: J
authors.lastname: Imrich
authors.affiliation: Department of Organic Chemistry, Pavol Jozef Šafárik University, Moyzesova 11, 041 57 Košice, Slovak Republic.
authors.forename: L
authors.initials: L
authors.lastname: Janovec
authors.affiliation: Institute of Normal and Pathological Physiology, Sienkiewiczova 1, 813 71 Bratislava, Slovak Republic.
authors.forename: I
authors.initials: I
authors.lastname: Dovinová
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 / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D048289:Imidazolidines; D017319:Photosensitizing Agents
keywords: Acridine; Anticancer; PDT; Photosensitizers