**5. Proteasome inhibition**

Proteasome inhibitors are considered as a potential remedy for cancer, inflammation-related disorders and neurodegenerative diseases. Proteasome inhibitors can cause cellular apoptosis in proliferating cancer cells by affecting various short-lived proteins, resulting in inhibition of NF-ĸB activity, increased activity of p53 and Bax proteins, and accumulation of cyclin- dependent kinase inhibitors p27 and p21 [Moriyoshi et al., 2004; Van Waes et al., 2007]. Preclinical studies show that malignant, transformed, and proliferating cells are more susceptible to proteasome inhibition than cells in a resting state [Adams, 2002; Sherr, 1996].

Bortezomib is the first inhibitor of the ubiquitin-proteasome pathway to enter clinical studies [Adams et al., 1999; Richardson et al., 2003]. On the basis of a large, multicenter phase II clinical trial in which approximately one third of patients with advanced multiple myeloma (MM) had a significant response to therapy with bortezomib, on May 13th 2003, the US Food and Drug Administration granted approval for use of this drug in the treatment of patients with MM [Richardson et al., 2003]. The promising preclinical and clinical activity exhibited by bortezomib in MM and non-Hodgkin lymphomas (NHL) has confirmed the proteasome as a relevant and important target in the treatment of cancer. Several proteasome inhibitors are being tested and are in the pre-clinical and clinical phase of testing.

In the case of RA, up-regulation of the most important pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, iNOS and endothelial cell adhesion molecules (e.g. vascular cell adhesion molecule 1 (VCAM-1)) are regulated by NF-κB [Van Waes et al., 2007; Han et al 1998]. Therefore RA qualifies as a potential target for proteasome inhibitors. *In vitro* and *in vivo* studies have presented encouraging results by the use of different proteasome inhibitors to reduce the NF-κB activation.

#### **5.1 Proteasome inhibitors**

Proteasome inhibitors include a variety of natural and chemically synthesized molecules which exclusively inhibit proteasome activity. The structure and function of some important classes of proteasome inhibitors are described here.
