Proteasome Inhibitors

Protein degradation by the proteasome complex represents a potential target for therapeutic interventions. Indeed, proteasome inhibitors have been available since 1994. The first clinical data from phase I studies became accessible in 2002. Four

Proteasome inhibitors (e.g. bortezomib)

Cell membrane



Fig. 1. Muscle wasting in man. An unknown stimulus, possibly TNF-a binding to its receptors, causes ubiquitin binding to myofibrils. These proteins are then directed to the proteasome complex. The proteasome releases peptides, which are further broken down to free amino acids by yet unidentified mechanisms. Several proinflammatory cytokines are known to induce proteasome activity while proteasome inhibitors block it classes of proteasome inhibitors have been described so far [26,27]:

1. Peptide aldehydes primarily inhibit the chy-motrypsin-like activity of the proteasome, which is one of its specific proteolytic sites. Removing the peptide aldehyde restores the proteolytic activity.

2. Lactacystin and its active derivative p-lactone are more specific, but irreversible inhibitors of the proteasome. They act as pseudosubstrates that are covalently bound to one of the sub-units of the proteasome [28].

3. Vinyl sulfone has been shown to inhibit the proteasome complex irreversibly in a similar manner to lactacystin [29]. In a human lymphoma cell line prolonged inhibition of the proteasome by vinyl sulfone led to the appearance of cell variants with a distinct proteolytic system [29].

4. Dipeptide boronic acid analogues have been shown to block proteasome activity via reversible binding to its active sites. Indeed, bortezomib (also known as PS-341) from this class of proteasome inhibitors is the only such drug that has been used in clinical trials so far. A phase I study in 43 patients with different types of advanced solid tumour malignancies showed a safe and reasonable treatment regimen with this substance [30]. Side-effects were diarrhoea and sensory neurotoxicity, both of which are dose-limiting toxicities. Unfortunately, the authors did not report differences in body weight before and after treatment. Another study revealed that in vivo administration of bortezomib induced proteasome inhibition in a time-dependent manner and that the inhibition was also related to both the dose in milligrams per square meter of body surface area and the absolute dose of bortezomib [31]. This study also revealed that patients treated with borte-zomib require careful monitoring of electrolyte abnormalities and late toxicities [31].

More recent work has illustrated the role of bortezomib in relapsed, refractory multiple myeloma [32]. In this multicentre, open-label, non-randomised phase II trial, 202 patients were enrolled and received 1.3 mg of bortezomib per square meter of body surface area twice weekly for up to eight cycles. The response rate was 35%. Myeloma protein became undetectable in seven patients, and in 12 patients myeloma protein was detectable only by immunofixation. Therefore, the authors of this study conclude that bortezomib is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy [32].

Peptide aldehydes, lactacystin and p-lactone have been shown to block up to 90% of the degradation of abnormal proteins and short-lived proteins in the cell [29]. Unfortunately, it is not possible to block specifically myofibril degradation in skeletal muscle.

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