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4, 9-Diazapyrenium derivatives as inducers of apoptosis and topoisomerase II poisons

4, 9-Diazapyrenium derivatives (BzDAP, FDAP, GDAP, JDAP, MDAP, m-MOST, p-MOST) are synthetic compounds acting on DNA level by double strand DNA intercalation between adjacent base pairs. Recently studied 4, 9-diazapyrenium derivatives (FDAP, GDAP and MDAP) showed antitumor activity against human malignant cell lines MIA PaCa-2, Hep-2, SKBr3, HeLa and SW620. Morpholigical changes and ladder DNA fragmentation indicated apoptosis as mode of cell death. The main objective of this study was to determine whether the FDAP, GDAP and m-MOST induce apoptosis in human tumor MIA PaCa-2 and Caco-2 cells, and to determine whether the all seven 4, 9-diazapyrenium derivatives stimulate topoisomerase II-mediated DNA cleavage. For detection of phosphatydilserine exposure from interior side of plasma membrane to the outher leaflet Annexin-V-fluorescein was used. In situ detection of DNA fragmentation was analyzed by TUNEL method. For screening of topisomerase II-targeted effects of 4, 9-diazapyrenium derivatives the cell-free assay was used. Strategy was based on alterations of electrophoretic mobility of pBR322 plasmid DNA due to connected action of Drosophila melanogaster topisomerase II and tested intercalative compounds. The results of phosphatidylserine exposure and DNA fragmentation investigations indicated apoptosis as mode of treated tumor cell's death. Examination of mechanism of action of 4, 9-diazapyrenium derivatives showed that tested compounds stimulate topoisomerase II-mediated DNA-cleavage. Hence, 4, 9-diazapyrenium derivatives can be considered as topoisomerase II poisons.

4; 9-Diazapyrenium derivatives; topoisomerase II

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