**6. Toxicity**

The clinical application of proteasome inhibitors might be limited due to potential side effects of available compounds following chronic administration. Toxic affects might result from the accumulation of ubiquitinated proteins after inhibition of the 26S proteasome. The proteasome inhibitor bortezomib (PS-341) induced mild-to-moderate neurotoxic effects in rats [Cavaletti et al., 2007] and peripheral sensory neuropathy in cancer patients when given this compound chronically [Cata et al., 2006]. The features of bortezomib neuropathy are characteristic for a small fiber neuropathy and are characterized by a more sensory than motor neuropathy. Several observations, however, argue against these possibilities. First, in rats, the neurotoxic effects were observed when bortezomib was administered at maximum tolerated, sub-lethal doses in rats [Cavaletti et al., 2007]. Bortezomib might have induced neurotoxic effects because of the presence of a component in its activity that is blocked by the polyhydroxyl compound Tiron, this component is not involved in MG132 activity [Fernandez et al., 2006]. No effects of MG132 toxicity were apparent on motor performance during rotarod, posture, gait, exploratory and locomotor activity, or on cell death in the spinal cord, when MG132 was administered at higher doses [Ossipov et al., 2006]. Moreover, MG132 treated animals gained significantly more body weight than the vehicle treated arthritic controls [Ahmed et al., 2010]. These results indicate that proteasome inhibitor MG132 given at therapeutically relevant doses was well tolerated. This is a significant finding as the proteasome plays a central role in many intracellular functions and its inhibition might theoretically be expected to induce numerous side effects.
