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Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis.

Publication ,  Journal Article
DiGiuseppe, JA; Weng, LJ; Yu, KH; Fu, S; Kastan, MB; Samid, D; Gore, SD
Published in: Leukemia
August 1999

The aromatic fatty acid phenylbutyrate (PB) induces cytostasis, differentiation, and apoptosis in primary myeloid leukemic cells at clinically achievable concentrations. In the present study, we have investigated the structural and cellular basis for PB-induced cytostasis, using the ML-1 human myeloid leukemia cell line as a model system. PB induced a dose-dependent increase in cells in G1 with a corresponding decrease in cells in S-phase of the cell cycle. At comparable doses, PB induced expression of CD11b, indicating myeloid differentiation. At higher doses, the drug induced apoptosis. The antitumor activity was independent of the aromatic ring, as butyric acid (BA) was of equal or greater potency at producing these biological changes. In contrast, shortening of the fatty acid carbon chain length, as demonstrated with phenylacetate (PA), significantly diminished drug potency. Consistent with their effects on cell cycle, PB and BA, but not PA, induced the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1), and led to the appearance of hypophosphorylated Rb, suggesting a role for p21(WAF1/CIP1) in PB-induced cytostasis. Therefore, it appears that the fatty acid moiety of PB, rather than its aromatic ring, is critical for its activity in myeloid leukemic cells. These data provide a potential mechanistic basis for the increased potency of PB over PA previously demonstrated in primary leukemic samples, and support the further clinical development of PB in the treatment of hematologic malignancies.

Duke Scholars

Published In

Leukemia

DOI

ISSN

0887-6924

Publication Date

August 1999

Volume

13

Issue

8

Start / End Page

1243 / 1253

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Phenylbutyrates
  • Leukemia, Myeloid
  • Immunology
  • Humans
  • G1 Phase
  • Dose-Response Relationship, Drug
  • Cell Division
  • Cell Differentiation
 

Citation

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DiGiuseppe, J. A., Weng, L. J., Yu, K. H., Fu, S., Kastan, M. B., Samid, D., & Gore, S. D. (1999). Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis. Leukemia, 13(8), 1243–1253. https://doi.org/10.1038/sj.leu.2401471
DiGiuseppe, J. A., L. J. Weng, K. H. Yu, S. Fu, M. B. Kastan, D. Samid, and S. D. Gore. “Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis.Leukemia 13, no. 8 (August 1999): 1243–53. https://doi.org/10.1038/sj.leu.2401471.
DiGiuseppe JA, Weng LJ, Yu KH, Fu S, Kastan MB, Samid D, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis. Leukemia. 1999 Aug;13(8):1243–53.
DiGiuseppe, J. A., et al. “Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis.Leukemia, vol. 13, no. 8, Aug. 1999, pp. 1243–53. Pubmed, doi:10.1038/sj.leu.2401471.
DiGiuseppe JA, Weng LJ, Yu KH, Fu S, Kastan MB, Samid D, Gore SD. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis. Leukemia. 1999 Aug;13(8):1243–1253.

Published In

Leukemia

DOI

ISSN

0887-6924

Publication Date

August 1999

Volume

13

Issue

8

Start / End Page

1243 / 1253

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Phenylbutyrates
  • Leukemia, Myeloid
  • Immunology
  • Humans
  • G1 Phase
  • Dose-Response Relationship, Drug
  • Cell Division
  • Cell Differentiation