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Histone Deacetylase Inhibitors Suppress the Inducibility of Nuclear Factor-B by Tumor Necrosis Factor- Receptor-1 Down-regulation

Therapeutic Area Oncology, ALTANA Pharma AG, Konstanz, Germany

Requests for reprints: Markus Boehm, ALTANA Pharma AG, RDR/P3, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany. Phone: 49-7531-844-537; Fax: 49-7531-849-4537; E-mail: markus.boehm{at}altanapharma.com.

Recently, the inhibition of histone deacetylase (HDAC) enzymes has attracted attention in the oncologic community as a new therapeutic opportunity for hematologic and solid tumors including non–small cell lung cancer (NSCLC). In hematologic malignancies, such as diffuse large B-cell lymphoma, the HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA), has recently entered phase II and III clinical trials. To further advance our understanding of their action on tumor cells, we investigated the possible effect of HDI treatment on the functionality of the nuclear factor-B (NF-B) pathway in NSCLC. We found that in the NSCLC cell lines, A549 and NCI-H460, the NF-B pathway was strongly inducible, for example, by stimulation with tumor necrosis factor- (TNF-). Incubation of several NSCLC cell lines with HDIs resulted in greatly reduced gene expression of TNF- receptor-1. HDI-treated A549 and NCI-H460 cells down-regulated TNF- receptor-1 mRNA and protein levels as well as surface exposure, and consequently responded to TNF- treatment with reduced IKK phosphorylation and activation, delayed IB- phosphorylation, and attenuated NF-B nuclear translocation and DNA binding. Accordingly, stimulation of NF-B target gene expression by TNF- was strongly decreased. In addition, we observed that SAHA displayed antitumor efficacy in vivo against A549 xenografts grown on nude mice. HDIs, therefore, might beneficially contribute to tumor treatment, possibly by reducing the responsiveness of tumor cells to the TNF--mediated activation of the NF-B pathway. These findings also hint at a possible use of HDIs in inflammatory diseases, which are associated with the overproduction of TNF-, such as rheumatoid arthritis or Crohn's disease. (Cancer Res 2006; 66(10): 5409-18)

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