Dynamic effect of bortezomib on nuclear factor-kappaB activity and gene expression in tumor cells.

Authors:
Sung MH, Bagain L, Chen Z, Karpova T, Yang X, Silvin C, Voss TC, McNally JG, Van Waes C, Hager GL
Associated Labs:
Dan Rockey Laboratory (National Institute of Health)
Mol Pharmacol. 2008 Nov . 74(5):1215-22.
PMID: 18684839
Nuclear factor-kappaB (NF-kappaB) influences the initiation, progression, and maintenance of diverse cancer types. Despite current therapeutic efforts to block hyperactive NF-kappaB in cancer cells, the in vivo effects of a drug upon this complex pathway are unclear. We monitored NF-kappaB 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-alpha-induced oscillation of NF-kappaB was echoed by equally dynamic reporter expression rate. Bortezomib is a proteasome inhibitor whose anticancer action is partly mediated through inhibition of NF-kappaB. 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.

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