The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apoptosis in human myeloid leukemia cells through a tumor necrosis factor-alpha-mediated process

Exp Cell Res. 2002 Jul 1;277(1):31-47. doi: 10.1006/excr.2002.5548.


Interactions between the histone deacetylase inhibitor sodium butyrate (SB) and phorbol 12-myristate 13-acetate (PMA) were examined in human myeloid leukemia cells (U937 and HL-60). Exposure of U937 cells to 1 mM SB and 1 nM PMA (24 h) markedly induced caspase activation and apoptosis, events accompanied by impaired differentiation induction (e.g., reduced plastic adherence and diminished expression of CD11b) as well as reduced clonogenic survival. The PKC inhibitor GF109203X blocked SB-/PMA-mediated apoptosis. Comparable results were obtained in HL-60 cells. Apoptosis was associated with early procaspase 8 activation and Bid cleavage, accompanied by pronounced mitochondrial damage (e.g., loss of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release). Neutralization of endogenous TNFalpha by a human soluble TNF receptor substantially blocked SB-/PMA-induced cytochrome c release and apoptosis. Consistent with this, ectopic expression of a mutant dominant-negative caspase 8 or CrmA resulted in a significant decrease in SB-/PMA-induced apoptosis, whereas Bcl-2 overexpression did not. SB/PMA treatment also triggered a decline in the S and G(2)M populations, and dephosphorylation of p34(cdc2). These results indicate that SB interacts with low concentrations of PMA to induce apoptosis in human leukemia cells and that this process proceeds through a PKC-/TNFalpha-dependent pathway in which procaspase 8 and Bid activation play key roles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Butyric Acid / pharmacology*
  • Drug Synergism
  • Enzyme Activation
  • HL-60 Cells
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Leukemia, Myeloid / metabolism*
  • Leukemia, Myeloid / pathology
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction*
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • U937 Cells


  • Histone Deacetylase Inhibitors
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Butyric Acid
  • Tetradecanoylphorbol Acetate