Abstract
Nuclear factor-κB (NF-κB) influences the initiation, progression, and maintenance of diverse cancer types. Despite current therapeutic efforts to block hyperactive NF-κB in cancer cells, the in vivo effects of a drug upon this complex pathway are unclear. We monitored NF-κB activity and a fast-expressing reporter level simultaneously in head and neck squamous carcinoma cells by quantitative live microscopy. The real-time single cell assay revealed the tumor necrosis factor-α-induced oscillation of NF-κB was echoed by equally dynamic reporter expression rate. Bortezomib is a proteasome inhibitor whose anticancer action is partly mediated through inhibition of NF-κB. When administered to preactivated cells, the drug gave rise to distinct inhibition dynamics, with discrete pulses of reporter induction remaining for hours. These findings suggest that, contrary to a simplistic presumption for a pathway “blockade,” the network dynamics and the intracellular pharmacokinetics of the inhibitor must be critically evaluated in developing strategies for optimal intervention of oncogenic pathways.
Footnotes
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This work was supported by National Institute on Deafness and Other Communication Disorders intramural project Z01-DC-00016 and by the National Institutes of Health Intramural Research Program for Center for Cancer Research, National Cancer Institute. C.V.W. has received bortezomib and clinical trial support under a National Institutes of Health-approved Cooperative Research and Development Agreement with Millennium Pharmaceuticals.
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ABBREVIATIONS: NF-κB, nuclear factor-κB; IκB, inhibitor of κB; IKK, IκB kinase; IL, interleukin; PS-341, [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid; HNSCC, head and neck squamous cell carcinoma; TNF, tumor necrosis factor; EGFP, enhanced green fluorescent protein; EMEM, Eagle's minimal essential medium; DAPI, 4,6-diamidino-2-phenylindole; ex, excitation; em, emission; GFP, green fluorescent protein.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received May 24, 2008.
- Accepted August 5, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Dynamic Effect of Bortezomib on Nuclear Factor-κB Activity and Gene Expression in Tumor Cells
