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.
Katona
Klára
K
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.
Herczegh
Pál
P
Kappelmayer
János
J
Fésüs
László
L
Aradi
Janos
J
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