Butyric acid and pivaloyloxymethyl butyrate, AN-9, a novel butyric acid derivative, induce apoptosis in HL-60 cells.
A novel butyric acid derivative, pivaloyloxymethyl butyrate, AN-9, was previously shown to be a potent differentiating agent. AN-9 exerts a significant anticancer activity in vitro and in vivo. In all the activities examined, AN-9 was more potent than butyric acid. Here we show that AN-9 and butyric acid induce cell death by apoptosis. Exposure of HL-60 cells to butyric acid and AN-9 decreased cell numbers and induced cell differentiation and the appearance of typical apoptotic features. Induction of apoptosis and/or differentiation by AN-9 and butyric acid was dependent on the concentration and the time of exposure to the drugs. The advantage of AN-9 over butyric acid was further confirmed. Apoptosis induced by AN-9 occurred after a shorter exposure and at lower drug concentrations than that induced by butyric acid. Apoptosis by AN-9 was accompanied by reduction in Bcl-2 expression. Preincubation with antioxidants did not protect HL-60 cells from apoptosis induced by AN-9. HL-60 cells that were induced to differentiate by preincubation with retinoic acid or low AN-9 concentrations were more resistant to apoptosis, induced later by high concentrations of AN-9, than were undifferentiated cells.
Zimra
Y
Y
Division of Hematology, Rabin Medical Center, Petach Tikava, Israel.
Wasserman
L
L
Maron
L
L
Shaklai
M
M
Nudelman
A
A
Rephaeli
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002452:Cell Count / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects*; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D002087:Butyrates; D004273:DNA, Neoplasm; D019253:Proto-Oncogene Proteins c-bcl-2; D020148:Butyric Acid; C070441:pivalyloxymethyl butyrate