PT  - JOURNAL ARTICLE
AU  - Myong-Hee Sung
AU  - Lorena Bagain
AU  - Zhong Chen
AU  - Tatiana Karpova
AU  - Xinping Yang
AU  - Christopher Silvin
AU  - Ty C. Voss
AU  - James G. McNally
AU  - Carter Van Waes
AU  - Gordon L. Hager
TI  - Dynamic Effect of Bortezomib on Nuclear Factor-κB Activity and Gene Expression in Tumor Cells
AID  - 10.1124/mol.108.049114
DP  - 2008 Nov 01
TA  - Molecular Pharmacology
PG  - 1215--1222
VI  - 74
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/74/5/1215.short
4100  - http://molpharm.aspetjournals.org/content/74/5/1215.full
SO  - Mol Pharmacol2008 Nov 01; 74
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics