Received for publication May 27, 2008.
Revised August 4, 2008.
Accepted for publication August 5, 2008.

Dynamic Effect of Bortezomib on NF-B Activity and Gene Expression in Tumor Cells

Abstract

NF-B influences the initiation, progression, and maintenance of diverse cancer types. Despite current therapeutic efforts to block hyperactive NF-B in cancer cells, the in vivo effects of a drug upon this complex pathway are unclear. We monitored NF-B 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 TNF- induced oscillation of NF-B was echoed by equally dynamic reporter expression rate. Bortezomib is a proteasome inhibitor whose anti-cancer action is partly mediated through inhibition of NF-B. When administered to pre-activated 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.

Key words: Tumor necrosis factor, NFkappaB, Thermodynamic and kinetic processes and modeling, Optical spectroscopy (fluorescence, DC, etc.), Regulation of gene expression, Oncogenes, Pharmacokinetics, metabolism and activation