Deoxy-adenosine-monophosphate (dAMP) di-n-butylester induces apoptosis by increasing the dATP level in HL-60 cells.
Deoxy-ATP is a potent inducer of apoptosis. We intended to synthesize a lipophilic dAMP derivative which, according to our working hypothesis penetrates into the cell, is converted to dAMP by intracellular esterases and to dATP by nucleotide kinases. We synthesized dAMP-di-n-butylester (DAB) and tested it. We found that it fulfills the above-described expectations. DAB treatment decreases the viability of HL-60 cells, increases the dATP concentration and induces apoptogenic cytochrome c release from mitochondria with concomitant elevation of caspase-9 activity. Our results indicate that use of dAMP derivatives with masked phosphate may be a feasible approach for pharmacological elevation of intracellular dATP and induction of apoptosis.
Department of Biochemistry and Molecular Biology, Medical and Health Science Center, Research Center for Molecular Medicine, University of Debrecen, Nagyerdei krt. 98. P.O. Box. 6, 4012 Debrecen, Hungary.
Klára
K
Katona
Pál
P
Herczegh
János
J
Kappelmayer
László
L
Fésüs
Janos
J
Aradi
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D003838:Deoxyadenine Nucleotides / Q000032:analysis* / Q000494:pharmacology*; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D011419:Propidium / Q000378:metabolism
D017304:Annexin A5; D003838:Deoxyadenine Nucleotides; D011419:Propidium; C012873:2'-deoxy-5'-adenosine monophosphate; D045304:Cytochromes c; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C026600:2'-deoxyadenosine triphosphate