Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy
| Autor: | Lýdia Čižeková, Z. Barbieriková, V. Brezová, Z. Ipóthová, A. Grolmusová, Helena Paulíková, Ladislav Janovec, Luba Hunakova, Ima Dovinova, Ján Imrich |
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| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
medicine.medical_treatment Clinical Biochemistry Pharmaceutical Science Photodynamic therapy Antineoplastic Agents medicine.disease_cause Imidazolidines Biochemistry Flow cytometry chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery medicine Animals Humans Molecular Biology Cells Cultured Cell Proliferation Photosensitizing Agents medicine.diagnostic_test Cell Death Dose-Response Relationship Drug Molecular Structure Cell growth Chemistry Singlet oxygen Organic Chemistry Cell Cycle Cell cycle Molecular biology Comet assay Oxidative Stress Photochemotherapy NIH 3T3 Cells Molecular Medicine Acridines Drug Screening Assays Antitumor Lysosomes Genotoxicity |
| Zdroj: | Bioorganicmedicinal chemistry. 22(17) |
| ISSN: | 1464-3391 |
| Popis: | 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 (>300 nm) 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 (72 h incubation) after irradiation of A2780 cells (365 nm, 1.05 J/cm2). The photocytotoxicity seems to be associated with oxidative stress. Concerning the cell cycle, flow cytometry showed an arrest in the S-phase already 4 h 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. |
| Databáze: | OpenAIRE |
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