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Pharmacological inhibitors of NF-κB accelerate apoptosis in chronic lymphocytic leukaemia cells

Lookup NU author(s): Professor Derek Mann

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Abstract

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 V(H) 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 NH(2)-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.Oncogene advance online publication, 21 August 2006; doi:10.1038/sj.onc.1209897.


Publication metadata

Author(s): Pickering BM, Mel Sde, Lee M, Howell M, Habens F, Dallman CL, Neville LA, Potter KN, Mann J, Mann DA, Johnson PW, Stevenson FK, Packham G

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2006

Volume: 26

Issue: 8

Pages: 1167-1177

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

Publisher: Nature Publishing Group

URL: http://www.nature.com/onc/journal/v26/n8/pdf/1209897a.pdf

DOI: 10.1038/sj.onc.1209897


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