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

J. A. DiGiuseppe, L. J. Weng, K. H. Yu, S. Fu, M. B. Kastan, D. Samid, S. D. Gore

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1243-1253
Number of pages11
JournalLeukemia
Volume13
Issue number8
StatePublished - 1999

Fingerprint

Phenylbutyrates
Myeloid Leukemia
Myeloid Cells
Apoptosis
Butyric Acid
Fatty Acids
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p21
Hematologic Neoplasms
S Phase
Pharmaceutical Preparations
Carbon

Keywords

  • Acute myeloid leukemia
  • Cytostatic agents
  • Differentiation therapy
  • ML-1 cells
  • Myelodysplasia

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

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.

Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells : Structure-function analysis. / DiGiuseppe, J. A.; Weng, L. J.; Yu, K. H.; Fu, S.; Kastan, M. B.; Samid, D.; Gore, S. D.

In: Leukemia, Vol. 13, No. 8, 1999, p. 1243-1253.

Research output: Contribution to journalArticle

DiGiuseppe, JA, Weng, LJ, Yu, KH, Fu, S, Kastan, MB, Samid, D & Gore, SD 1999, 'Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: Structure-function analysis', Leukemia, vol. 13, no. 8, pp. 1243-1253.
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;13(8):1243-1253.
DiGiuseppe, J. A. ; Weng, L. J. ; Yu, K. H. ; Fu, S. ; Kastan, M. B. ; Samid, D. ; Gore, S. D. / Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells : Structure-function analysis. In: Leukemia. 1999 ; Vol. 13, No. 8. pp. 1243-1253.
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