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A few words on proteasome

Most cellular proteins have a limited lifespan from a few minutes to a few weeks. The proteins are destroyed in two different ways: lysosomial system (10-20% superficial proteins) and proteasome system (close to 80% of intracellular proteins).

In order to be destroyed by proteasome, the proteins are first of all bound to various enzymes called ubiquitin, (of which there are three types: E1, E2, E3). The role of these ubiquitins is not limited to the destruction of proteins but probably also involves their intracytoplasmic transportation.

Once the protein has been ubiquitinylated, it is destroyed by a sort of incinerator; the proteasome, composed of four rings with 7 subunits.

he precise action is known for three of them: pseudo-caspase activity, trypsine activity, chymotrypsine activity.

Thus, proteasome is the central regulation point for many proteins implied in the carcinogenesis process. For instance, the following diagram shows its action on transcription factor NFκB.

[1] The NFκB transcription factor is bound to its inhibitor IκBα which prevents many of the necessary processes for cell division. [2] Under various external (or internal) stimuli, the inhibitor IκBα is ubiquitinylated. [3] This inhibitor is then destroyed in the proteasome. [4] The NFκB transcription factor is free. [5] It penetrates into the nucleus and exerts its transcription factor activity for various genes, in particular to inhibit apoptosis.

Inhibitors of proteasome

Cancer cells appear to have the capacity to retain a good part of their proteolysis machinery in order to react, like normal cells, and repair the chemotherapy aggression. They can also degrade the suppressive proteins or activate protooncogenes (just like the transcription factor NFκB).

The use of definitive inhibitors of proteasome would probably be too dangerous for the patient's whole organism.

Transitory inhibitors have been synthesised. The most studied molecule is boron acid which blocks the threonine protease activity of chymotrypsine, thus reducing the degradation of proteins regulating the cell cycle like IκBα, cyclin E, p53 protein or p27 protein. The use of these proteasome inhibitors leads to the diminution of cell multiplication and induction of apoptosis.

The most advanced molecule in clinical setting is bortezomib.

Biochemical structure of bortezomib

The activity of bortezomib might be explained by its preferential binding with the chymotrypsine-like sub-unit of proteasome. It induces apoptosis which is proportional to the duration of administration and the concentration of bortezumib. In some cells (myeloma cells), the transcription factor NFκB is blocked by the inhibition of phosphorylation of inhibitor IκBα. For other cells (prostate cancer cells), the division is blocked between G2 and M phases by the stabilisation of p53 protein.

Possible action of Bortezomib on proteasome subunits.

Clinical activity

The first clinical studies concern myeloma. In a major phase II study, Bortezomib was administered at a dosage of 1.3 mg/m² to patients relapsing after several chemotherapy regimens. A 35% response rate was observed with 10% of complete responses. Duration of responses was around 12 months.

Toxicity was light: thrombocytopaenia, neutropaenia and muscle fatigue. In other studies, limiting toxicity seems to be diarrhoea and hypotension.

Many studies are currently in progress in breast cancer, hormone independent prostate cancer, lung cancer and lymphoma.

This is only the beginning of study of such new therapeutic molecules with new targets.