Inhibitors of DNA polymerase beta: activity and mechanism.
Bioassay-guided fractionation of extracts prepared from Couepia polyandra and Edgeworthia gardneri resulted in the isolation of the DNA polymerase beta (pol beta) inhibitors oleanolic acid (1), edgeworin (2), betulinic acid (3), and stigmasterol (4). Study of these pol beta inhibitors revealed that three of them inhibited both the lyase and polymerase activities of DNA polymerase beta, while stigmasterol inhibited only the lyase activity. Further investigation indicated that the four inhibitors had substantially different effects on the DNA-pol beta binary complex that is believed to be an obligatory intermediate in the lyase reaction. It was found that the inhibitors potentiated the inhibitory action of the anticancer drug bleomycin in cultured A549 cells, without any influence on the expression of pol beta in the cells. The results of the unscheduled DNA synthesis assay support the thesis that the potentiation of bleomycin cytotoxicity by DNA pol beta inhibitors was a result of an inhibition of DNA repair synthesis.
Gao
Zhijie
Z
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Maloney
David J
DJ
Dedkova
Larisa M
LM
Hecht
Sidney M
SM
D001761:Bleomycin / Q000633:toxicity; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D012545:Schiff Bases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D003374:Coumarins; D004791:Enzyme Inhibitors; D012545:Schiff Bases; C093655:edgeworin; D001761:Bleomycin; D004247:DNA; D019951:DNA Polymerase beta; D045643:DNA Repair Enzymes