Coadministration of UCN-01 with MEK1/2 inhibitors potently induces apoptosis in BCR/ABL+ leukemia cells sensitive and resistant to ST1571

Cancer Biol Ther. Nov-Dec 2002;1(6):674-82. doi: 10.4161/cbt.319.

Abstract

Interactions between the PKC and Chk1 inhibitor UCN-01 and pharmacologic MEK1/2 inhibitors (e.g., U0126, PD184352) were examined in Bcr/Abl(+) = human leukemia cells (K562, LAMA 84) sensitive and resistant to the Bcr/Abl kinase inhibitor STI571. Coexposure of K562 cells to UCN-01 (e.g., 100 nM) or U0126 (30 microM) resulted in a marked increase in mitochondrial injury (e.g., release of cytochrome c; loss of deltapsi(m)) and apoptosis. Similar results were obtained in other Bcr/Abl(+) cells (e.g., LAMA 84, BV-173) and with other MEK1/2 inhibitors (e.g., PD184352). Exposure of K562 cells to UCN-01 resulted in activation of ERK, an effect that was abrogated by co-administration of MEK1/2 inhibitors. Coadminstration of UCN-01 with U0126 produced multiple perturbations in signal transduction/cell cycle regulatory pathways, including diminished expression of Bcr/Abl, Mcl-1, cylin D(1), and activation of JNK and p34(cdc2). Coadministration of the JNK inhibitor SP600125 attenuated UCN-01/MEK inhibitor- associated lethality, suggesting a functional role for JNK activation in enhanced lethality. Finally, UCN-01 and MEK1/2 inhibitors effectively induced apoptosis in Bcr/Abl(+) cells (e.g., K562 and LAMA 84) overexpressing Bcr/Abl and resistant to STI571. These findings indicate that BcrAbl(+) leukemia cells are sensitive to a strategy combining UCN-01 with MEK/ERK inhibitors that simultaneously disrupts two signaling pathways.

MeSH terms

  • Alkaloids / administration & dosage
  • Anthracenes / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Apoptosis / drug effects*
  • Benzamides / administration & dosage
  • Blotting, Western
  • Butadienes / administration & dosage
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cyclin D1 / metabolism
  • Cytochrome c Group / drug effects
  • Cytochrome c Group / metabolism
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / administration & dosage
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imatinib Mesylate
  • K562 Cells / pathology
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Membrane Potentials / drug effects
  • Mitochondria / drug effects
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Nitriles / administration & dosage
  • Piperazines
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2*
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects
  • Staurosporine / analogs & derivatives

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Alkaloids
  • Anthracenes
  • Benzamides
  • Butadienes
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Nitriles
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • U 0126
  • Cyclin D1
  • pyrazolanthrone
  • 7-hydroxystaurosporine
  • Imatinib Mesylate
  • Poly(ADP-ribose) Polymerases
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • Caspases
  • Staurosporine