Comparison between the effect of butyric acid and its prodrug pivaloyloxymethylbutyrate on histones hyperacetylation in an HL-60 leukemic cell line.
A butyric acid pro-drug, pivaloyloxymethyl butyrate, AN-9, developed in our laboratory, was previously shown to act as a differentiation-inducing and an anti-cancer agent. In this study we have shown that both AN-9 and butyric acid caused a transient hyperacetylation of histones, which returned to basal levels after 6 and 12 hr, respectively. This activity precedes the induction of differentiation elicited by both agents. AN-9 induced acetylation of histones at a concentration one order of magnitude lower than butyric acid. Pre-treatment of the cells with esterase(s) inhibitors diminished the ability of AN-9 to inhibit proliferation and induce differentiation. The above suggests that the intracellular release of butyric acid fragment, from the pro-drug, is catalyzed by cellular esterase(s).
Aviram
A
A
Basil and Gerald Felsenstein Medical Research Center, Beilinson Campus, Petach-Tikva, Israel.
Zimrah
Y
Y
Shaklai
M
M
Nudelman
A
A
Rephaeli
A
A
D000107:Acetylation; D000814:Aniline Compounds / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D006657:Histones / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D002087:Butyrates; D006657:Histones; D009943:Organophosphorus Compounds; D011355:Prodrugs; D020148:Butyric Acid; C070441:pivalyloxymethyl butyrate; C068798:4-aminophenylphosphate