Effects of brequinar and ciprofloxacin on de novo nucleotide biosynthesis in mouse L1210 leukemia.
Exposure of mouse L1210 leukemia cells to 25 microM brequinar for 4 h results in large accumulations of N-carbamyl-L-aspartate and L-dihydroorotate to cellular concentrations of 8.5 mM and 0.8 mM, respectively, while UTP and CTP decrease to 4% of their initial levels; incorporation of [14C]bicarbonate into nucleic acids (DNA and RNA) was decreased to 47%. These data provide direct evidence for inhibition of DHO dehydrogenase by brequinar in growing cells. Exposure of leukemia cells to 200 microM ciprofloxacin for 4 h did not affect de novo pyrimidine nucleotide biosynthesis or the incorporation of [14C]bicarbonate into nucleic acids but resulted in a general decrease in nucleoside triphosphates, with concomitant accumulation of nucleoside mono- and diphosphates (the adenylate energy charge decreased from 0.89 to 0.69), consistent with inhibition of the electron transport chain or uncoupling of oxidative phosphorylation.
Lyons
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SD
Department of Biochemistry, University of Sydney, NSW, Australia.
Christopherson
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RI
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004081:Dihydroorotate Oxidase / Q000037:antagonists & inhibitors*; D004790:Enzyme Induction; D007939:Leukemia L1210; D051379:Mice; D009711:Nucleotides / Q000096:biosynthesis*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D011798:Quinaldines
D001713:Biphenyl Compounds; D002939:Ciprofloxacin; D004273:DNA, Neoplasm; D004081:Dihydroorotate Oxidase; D009711:Nucleotides; D012334:RNA, Neoplasm; C046943:brequinar; D011798:Quinaldines