Coadministration of UCN-01 with MEK1/2 inhibitors potently induces apoptosis in BCR/ABL+ leukemia cells sensitive and resistant to ST1571.
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.
Yu
Chunrong
C
Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia 23298, USA.
Dai
Yun
Y
Dent
Paul
P
Grant
Steven
S
D000470:Alkaloids / Q000008:administration & dosage; D000873:Anthracenes / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000008:administration & dosage; D015153:Blotting, Western; D002070:Butadienes / Q000008:administration & dosage; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000473:pathology; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage; D010879:Piperazines; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000470:Alkaloids; D000873:Anthracenes; D001549:Benzamides; D002070:Butadienes; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009570:Nitriles; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; C113580:U 0126; D019938:Cyclin D1; C432165:pyrazolanthrone; C054852:7-hydroxystaurosporine; D000068877:Imatinib Mesylate; D011065:Poly(ADP-ribose) Polymerases; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D019311:Staurosporine