Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

Leukemia. 2005 Sep;19(9):1579-89. doi: 10.1038/sj.leu.2403868.


Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34+ cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34+ bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21CIP1, Bcr/Abl, and cyclin D1, and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21CIP1 downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Retracted Publication

MeSH terms

  • Antigens, CD34 / drug effects
  • Antigens, CD34 / metabolism
  • Apoptosis / drug effects
  • Benzamides / pharmacology*
  • Bone Marrow Cells / drug effects
  • Butadienes / pharmacology
  • Butyrates / pharmacology
  • Caspases / drug effects
  • Caspases / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Fusion Proteins, bcr-abl / drug effects
  • Fusion Proteins, bcr-abl / metabolism
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Nitriles / pharmacology
  • Vorinostat


  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Antigens, CD34
  • Benzamides
  • Butadienes
  • Butyrates
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Nitriles
  • U 0126
  • Vorinostat
  • Fusion Proteins, bcr-abl
  • Mitogen-Activated Protein Kinase Kinases
  • Caspases