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Photosensitization by anticancer agents: 11. Mechanisms of photosensitization of human leukemic cells by diaminoanthraquinones: Singlet oxygen and radical reactions



Photosensitization by anticancer agents: 11. Mechanisms of photosensitization of human leukemic cells by diaminoanthraquinones: Singlet oxygen and radical reactions



Journal of Photochemistry and Photobiology B Biology 15(4): 317-335



The synthesis of several aminoanthraquinone derivatives (AAQs), designed to suppress the dark toxicity and to promote more efficient cancer cell photosensitization for potential use in photodynamic therapy (PDT), is described. The following AAQs were synthesized: 1-NH-2-4,5-(MeO)-2-AQ (1), 1,5-(NH-2)-2-4,(MeO)-2-AQ (2), 1,8-(NH-2)-2-4,5-(MeO)-2-AQ (3), and 1,5-(NHPhMe)-2-4,8-(MeO)-2-AQ (8). The agents exhibit strong absorption in the region 480-620 nm. Possible mechanisms of photosensitization were studied by measuring 1O-2 phosphorescence at 1270 nm, detecting superoxide radicals employing and electron paramagnetic resonance (EPR)-spin trapping technique, and measuring oxygen consumption during the photo-oxidation of a representative biological electron donor, NADH. Strong phosphorescence from 1O-2 was observed upon illumination of 2 and 3 in C-6H-6 (quantum yield of 0.25 and 0.5 respectively), and in EtOH (quantum yield of 0.23 and 0.34). The 1-amino-AQ (1) was the weakest 1O-2 sensitizer, with quantum yield of 0.13 in benzene. No phosphorescence was observed in EtOH. A superoxide radical was detected as a spin adduct of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) in irradiated benzene solutions of 1, 2 or 3 and DMPO. AAQs 2 and 3 sensitized photo-oxidation of NADH in H-2O/EtOH mixture with the intermediacy of singlet oxygen as judged by the effect of sodium azide on the photostimulated oxygen consumption. Evolution of O-2 upon addition of catalase to the illuminated solution confirmed the ultimate formation of hydrogen peroxide. These findings suggest that the (di)amino-dimethoxyanthraquinones might exert photosensitization via both Type I and Type II mechanisms. The AAQs were tested for their ability to photosensitize K562 human chronic myeloid leukemic cells ion culture. Viability was measured using the 3,4,5-diethylathiazol-2, 5-diphenyl tetrasolium blue assay, and DNA and possible membrane damage were assessed. The results for illuminating cells with light gt 475 nm show that for the 1,5-compounds, the presence of methoxy substituents at 4,8 positions reduces the dard toxicity from ID-50 of 23 of 250 mu-M and for the 1,8-compounds correspondingly from ID-50 of 53 to gt 300 mu-M. In the 1,5-series this decrease of the dark toxicity is accompanied by an increase in light-induced dose modification from 8.85 to 14.4. Differences exist in the mechanisms of cytotoxicity between the prototype phenolic AAQs and their methoxy counterparts. It appears that the cytotoxic action of the latter causes cell damage by the formation of a high proportion of alkali labile sites in addition to frank stand breaks. No evidence for membrane damage, as determined by transport of the model amino acid cycloleucine, could be observed even at supralethal doses.

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Accession: 009191568

Download citation: RISBibTeXText

PMID: 1331388

DOI: 10.1016/1011-1344(92)85138-k


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