Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.
Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.
Pickering
B M
BM
Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton, UK.
de Mel
S
S
Lee
M
M
Howell
M
M
Habens
F
F
Dallman
C L
CL
Neville
L A
LA
Potter
K N
KN
Mann
J
J
Mann
D A
DA
Johnson
P W M
PW
Stevenson
F K
FK
Packham
G
G
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D053453:Caspase 9 / Q000032:analysis / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004224:Diterpenes / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004224:Diterpenes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C047382:kamebakaurin; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D048670:MAP Kinase Kinase 4; D051997:ADP-ribosyl Cyclase 1; D053148:Caspase 3; D053453:Caspase 9