INTRODUCTION

Bortezomib is a reversible inhibitor of the 26S proteasome, a protein complex that degrades ubiquitinated proteins. Proteins entering the proteasome are stripped of their ubiquitin, and subsequently degraded through catalytic activities within the core of the proteasome. The compound bortezomib (PS-341) contains a boronate moiety linked to a dipeptide and has exceedingly high affinity, specificity, and selectivity for catalytic activity of the proteasome.

Nuclear factor-κB (NF-κB) is a transcription factor that is retained in the cytoplasm when it is bound to an inhibitory partner protein, IκB. When IκB undergoes regulated serine phosphorylation, it is ubiquitinated and degraded in the proteasome. The released NF-κB moves to the nucleus, where it induces the transcription of genes whose protein products block cell-death pathways, promote cell proliferation, and regulate the expression of adhesion molecules. Inhibition of IκB degradation by proteasome inhibitors keeps NF-κB in the cytoplasm, thereby preventing it from acting on nuclear DNA.

Modification of IκB also results in the sensitization of tumor cells to chemotherapeutic agents and radiation. However, the inhibition of the proteasome has other consequences, including decreased activation of the mitogen-activated protein kinase pathway and upregulation of p53 and the cell cycle inhibitor p27 [Figure 1]

|  Figure 1:Mechanism of action of bortezomib