Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK

Blood. 2005 Feb 15;105(4):1706-16. doi: 10.1182/blood-2004-07-2767. Epub 2004 Oct 19.


Interactions between the Chk1 inhibitor UCN-01 and the farnesyltransferase inhibitor L744832 were examined in human leukemia cells. Combined exposure of U937 cells to subtoxic concentrations of UCN-01 and L744832 resulted in a dramatic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary acute myeloid leukemia (AML) blasts. Coadministration of L744832 blocked UCN-01-mediated phosphorylation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), leading to down-regulation of phospho-cyclic adenosine monophosphate responsive element-binding protein (phospho-CREB) and -p90(RSK) and activation of p34(cdc2) and stress-activated protein kinase/ERK kinase/c-Jun N-terminal kinase (SEK/JNK). Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -glycogen synthase kinase-3 (-GSK-3), -p70(S6K), -mammalian target of rapamycin (-mTOR), -forkhead transcription factor (-FKHR), -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis but did not prevent activation of p34(cdc2) and JNK or inactivation of MEK/ERK and Akt. Enforced expression of myristoylated Akt but not constitutively active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01 and, in so doing, dramatically increase mitochondria-dependent apoptosis.

Publication types

  • 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.

MeSH terms

  • Acute Disease
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Checkpoint Kinase 1
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Farnesyltranstransferase
  • HL-60 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Jurkat Cells
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / enzymology
  • Leukemia, Myeloid / pathology
  • MAP Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System / drug effects*
  • Membrane Potentials / drug effects
  • Methionine / analogs & derivatives*
  • Methionine / toxicity
  • Mitochondria / drug effects
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt
  • Staurosporine / analogs & derivatives*
  • Staurosporine / metabolism*
  • Staurosporine / toxicity
  • U937 Cells


  • Enzyme Inhibitors
  • L 744832
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • 7-hydroxystaurosporine
  • Methionine
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • Protein Kinases
  • AKT1 protein, human
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Caspases
  • Staurosporine