Abstract:
:Apoptotic endonuclease G (EndoG) is responsible for DNA fragmentation both during and after cell death. Previous studies demonstrated that genetic inactivation of EndoG is cytoprotective against various pro-apoptotic stimuli; however, specific inhibitors for EndoG are not available. In this study, we have developed a high-throughput screening assay for EndoG and have used it to screen a chemical library. The screening resulted in the identification of two potent EndoG inhibitors, PNR-3-80 and PNR-3-82, which are thiobarbiturate analogs. As determined by their IC₅₀s, the inhibitors are more potent than ZnCl₂ or EDTA. They inhibit EndoG at one or two orders of magnitude greater than another apoptotic endonuclease, DNase I, and do not inhibit the other five tested cell death-related enzymes: DNase II, RNase A, proteinase, lactate dehydrogenase, and superoxide dismutase 1. Exposure of natural EndoG-expressing 22Rv1 or EndoG-overexpressing PC3 cells rendered them significantly resistant to Cisplatin and Docetaxel, respectively. These novel EndoG inhibitors have the potential to be utilized for amelioration of cell injuries in which participation of EndoG is essential.
journal_name
DNA Cell Bioljournal_title
DNA and cell biologyauthors
Jang DS,Penthala NR,Apostolov EO,Wang X,Crooks PA,Basnakian AGdoi
10.1089/dna.2014.2530subject
Has Abstractpub_date
2015-02-01 00:00:00pages
92-100issue
2eissn
1044-5498issn
1557-7430journal_volume
34pub_type
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