Acridin-3,6-dialkyldithiourea hydrochlorides as new photosensitizers for photodynamic therapy of mouse leukemia cells |
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| Affiliation: | 1. Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic;2. Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic;3. Department of Organic Chemistry, Faculty of Science, Pavol Jozef Šafárik University, Moyzesova 11, 041 01 Košice, Slovak Republic;4. Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava, Slovak Republic;5. Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovak Republic;1. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA;2. Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA;3. Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA;4. Department of Chemistry, Lehman College, The City University of New York, Bronx, NY 10468, USA;5. Department of Natural Sciences, LaGuardia Community College, City University of New York, New York, NY 11101, USA;6. Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji’nan, Shandong 250012, China;2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;3. Institute of Criminal Science and Technology, Ji’nan Public Security Bureau, Ji’nan 250100, China;4. School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, China;1. Research Institute of Labeling, FutureChem Co., Ltd, Seoul 04782, Republic of Korea;2. Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea;3. Global Drug Discovery—Molecular Imaging, Bayer Healthcare AG, 13353 Berlin, Germany;4. Department of Nuclear Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul 05505, Republic of Korea;1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt;3. Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ain Helwan, University Campus, 11795 Cairo, Egypt;4. Center for Scientific Excellence ‘Helwan Structural Biology Research (HSBR)’, Cairo, Egypt |
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| 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/cm2) 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). |
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| Keywords: | Photosensitizers Acridines Anticancer drugs Photodynamic therapy |
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