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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.

The Unfolded Protein Response in Amelogenesis and Enamel Pathologies

“…Despite this, the specific cellular response to 4-PB depends on cell context. For example, 4-PB can be pro-apoptotic in myeloid leukemia cells (DiGiuseppe et al, 1999 ) and prostate cancer cells (Melchior et al, 1999 ). The question as to whether 4-PB might have therapeutic value in treating AI was investigated when female mice heterozygous for the Amelx p.(Y64H) mutation were fed 4-PB in their diet.…”

Epigenetic therapy of leukemia: An update

“…36,37 Based on their preclinical study indicating a role of PB in differentiation and inhibition of growth of primary leukemia cells, 38,39 Gore et al explored the use of single agent PB in patients with MDS and AML. In the phase I trial, continuous 7 day infusion of PB was used (7/28 schedule: 7 days on, 21 days off schedule) in 11 patients with MDS and 16 patients with AML and a dose of 375 mg/kg/day was established as the maximally tolerated dose (MTD).…”

“…HDAC inhibition was not measured in these trials as these were initiated prior to the knowledge of HDAC inhibition by PB. 38,42 …”

Epigenetic Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemias

“…It has been effectively used to induce fetal erythropoiesis in patients with sickle cell anemia and β-thalassemia [105]. The aromatic ring does not contribute to the antitumor activity, as butyric acid is of equal or greater potency at producing these biological changes, while shortening of the fatty acid carbon chain length, as demonstrated with phenylacetate, significantly diminished drug potency [106]. After administration phenylbutyrate is metabolized to phenylacetate, then to phenylacetylglutamine and eliminated by urine [107].…”