title: Esterase inhibitors diminish the modulation of gene expression by butyric acid derivative, pivaloyloxymethyl butyrate (AN-9).
abstract: Pivaloyloxymethyl butyrate (AN-9) belongs to the family of acyloxyalkyl ester prodrugs of carboxylic acids which undergo intracellular hydrolysis to yield butyric acid (BA). We have previously shown that AN-9 and BA reduce the level of c-myc and enhance c-jun transcripts in HL-60 cells, and that the differentiation of these cells, induced by AN-9, is dependent on the presence of intracellular esterases. In this study we show that esterase inhibitors abolish the changes induced by AN-9 on c-myc and c-jun expression. In contrast, esterase inhibitors do not change the effects of BA on c-myc or c-jun. Interestingly, these inhibitors affect the modulation induced by both AN-9 and BA on the retinoblastoma tumor suppressor gene. These data suggest that AN-9 is indeed a prodrug of BA and that prior intracellular hydrolysis by esterases is material for AN-9 activity.
authors.affiliation: Institute of Hematology, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Rabizadeh
authors.forename: M
authors.initials: M
authors.lastname: Shaklai
authors.forename: L
authors.initials: L
authors.lastname: Eisenbach
authors.forename: A
authors.initials: A
authors.lastname: Nudelman
authors.forename: A
authors.initials: A
authors.lastname: Rephaeli
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D004336:Drug Antagonism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D016758:Genes, jun / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology*; D011292:Premedication
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002087:Butyrates; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D020148:Butyric Acid; C070441:pivalyloxymethyl butyrate; D010664:Phenylmethylsulfonyl Fluoride; C068798:4-aminophenylphosphate